A key event in NF-kappa-B activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kappa-B signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta (IKKb, IKBKB) in an IKK gamma (IKBKG, NEMO)-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta)). Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kappa-B.
",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-168140",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-168140"
}
]
},
{
"id": "R-HSA-168184",
"name": "Activated TAK1 mediates phosphorylation of the IKK Complex",
"equation": "",
"summary": "In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kappa-B by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha (IKKa, IKK1 or CHUK) and IKK beta (IKKb, IKK2, IKBKB) associated with a regulatory subunit NEMO (IKK gamma or IKBKG). Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. In the classical or canonical NF-kappa-B pathway, the activation of the IKK complex is dependent on the phosphorylation of IKKb (IKBKB) at its activation loop and the ubiquitination of IKBKG (NEMO) (Solt et al 2009; Li et al 2002). IKKb (IKBKB) is phosphorylated at Ser177 and Ser181 (Wang et al. 2001). IKBKG (NEMO) ubiquitination by TRAF6 is required for optimal activation of the IKK kinase activity; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination. Activated IKK complex phosphorylates IkB alpha (IkBa or NFKBIA) on Ser32 and Ser36 leading to K48-linked ubiquitination and proteasome-dependent degradation of IkB alpha. This leads to the release of active NF-kappa-B dimers.
This Reactome event shows phosphorylation of IKK beta (IKBKB) by TGF-\u03b2\u2013activated kinase 1 (TAK1), encoded by the MAP3K7 gene. TAK1 functions downstream of receptor signaling complexes in TLR, TNF-alpha and IL-1 signaling pathways (Xu & Lei 2021). TAK1 appears to be essential for IL-1-induced NF-kappa-B activation since a specific TAK1 inhibitor (5Z)-7-oxozeaenol prevents NF-kappa-B activation in human umbilical vein endothelial cells (HUVEC) (Lammel 2020); also, it prevents NF-kappa-B-mediated TNF production in human myeloid leukaemia U937 cells (Rawlins et al. 1999). TAK1 functions through assembling the TAK1 complex consisting of the coactivators TAB1 and either TAB2 or TAB3 (Shibuya et al. 1996, Sakurai et al. 2000; Xu & Lei 2021). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe (Sakurai et al. 2000; Brown et al. 2005). The TAK1 complex is regulated by polyubiquitination. The binding of TAB2 or TAB3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2, -3 by TRAF6 (Ishitani et al. 2003), which in turn results in conformational changes within the TAK1 complex. TAB2 or -3 is recruited to K63-linked polyubiquitin chains of receptor interacting protein (RIP) kinase RIP1 (RIPK1) via the Zinc finger domain of TAB2 or TAB3. RIPK1 functions as an essential component of inflammatory and immune signaling pathways. Ubiquitination of RIPK1 follows the recruitment of TRADD and TRAF2 or -5 (the latter functions as the E3 ubiquitin ligase, but also cIAP1,-2 can ubiquitinate RIPK1 as a response to TNF receptor engagement (Varfolomeev et al. 2008). The IKK complex is also recruited ubiquitin (Ub) chains via its Ub binding domain. Polyubiquitin chains may function as a scaffold for higher order signaling complexes bringing the TAK1 and IKK complexes in close proximity and allowing TAK1 to phosphorylate IKBKB (IKK2) (Kanayama et al. 2004).
The alternative (non-canonical) pathway can be activated via CD40, LT\u00dfR, BAFF, RANK, and is therefore limited to cells which express these receptors. It leads to NIK-mediated phosphorylation of IKKa (IKK1, CHUK), which phosphorylates the NFKB2 (p52) precursor p100, leading to the ubiquitin-dependent degradation of its C-terminal part (processing of p100 to the mature p52 subunit) and releasing the NFKB2:RelB complex (Sun 2017). In non-stimulated cells NIK is constitutively degraded by the cIAP1/2:TRAF2:TRAF3 Ub ligase complex; following stimulation, the complex is recruited to the respective receptor comlex where cIAPs ubiquitinates TRAF3, resulting it its degradation and stabilization of NIK. NIK then phosphorylates and activates IKK1 (CHUK), leading to the NFKB2:RelB complex activation (Sun 2017). TRAF3 deubiquitylation by OTUD7B downregulates the NIK-mediated NF-kappa-B activation. (Hu et al 2013). In addition, TAK1 has been shown to interact with NIK and with IKK2, and TAK1 can be stimulated by anti-apoptotic protein, XIAP (Hofer-Warbinek et al. 2000). XIAP is an NF-kB dependent gene, therefore its expression represents a positive regulatory circuit. NIK is also involved in the classical pathway, and is activated by TAK1 in the IL-1 signalling pathway (Ninomiya-Tsui et al. 1999) and Hemophilus influenzae-induced TLR2 signalling pathway (Shuto et al. 2001).
RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid (N) protein serves as a platform to enhance the interaction between TAK1 and IKK complexes promoting NF-kappa-B-dependent inflammatory responses (Wu Y et al. 2021).", "cellular_location": "cytosol", "input_participant_list": [], "output_participant_list": [ "R-HSA-202513" ], "enzyme_list": [ "O43318-1", "O15111-1", "Q9Y4K3-1", "O14920-1", "O43353-1", "P61088-1", "P51617-1" ], "evidence": [ { "id": "R-HSA-168184", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-168184" } ] }, { "id": "R-HSA-168910", "name": "RIP1 facilitates IKK complex phosphorylation", "equation": "", "summary": "RIP1 polyubiquitination was induced upon TNF- or poly(I-C) treatment of the macrophage cell line RAW264.7 and the U373 astrocytoma line (Cusson-Hermance et al 2005). These workers have suggested that RIP1 may use similar mechanisms to induce NF-kB in the TNFR1- and Trif-dependent TLR pathways.
RIP1 modification with Lys-63 polyubiquitin chains was shown to be essential for TNF-induced activation of NF-kB (Ea et al. 2006). It is thought that TRAF family members mediate this Lys63-linked ubiquitination of RIP1 (Wertz et al. 2004, Tada et al 2001, Vallabhapurapu and Karin 2009), which may facilitate recruitment of the TAK1 complex and thus activation of NF-kB. Binding of NEMO to Lys63-linked polyubiquitinated RIP1 is also required in the signaling cascade from the activated receptor to the IKK-mediated NF-kB activation (Wu et al. 2006).",
"cellular_location": "cytosol, endosome membrane",
"input_participant_list": [],
"output_participant_list": [
"R-HSA-177663"
],
"enzyme_list": [
"O15111-1",
"Q13546-1",
"O14920-1",
"Q9Y572-1"
],
"evidence": [
{
"id": "R-HSA-168910",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-168910"
}
]
},
{
"id": "R-HSA-198611",
"name": "AKT phosphorylates IKKalpha",
"equation": "",
"summary": "AKT mediates IKKalpha (Inhibitor of nuclear factor kappa B kinase subunit alpha) phosphorylation at threonine 23, which is required for NF-kB activation. NF-kB promoted gene transcription enhances neuronal survival.",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P31749-1",
"P31751-1",
"Q9Y243-1",
"O15111-1"
],
"evidence": [
{
"id": "R-HSA-198611",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-198611"
}
]
},
{
"id": "R-HSA-202500",
"name": "Activation of IKK complex",
"equation": "",
"summary": "The IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex.
IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on serine residues (S177 and S181) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.",
"cellular_location": "cytosol, plasma membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O43318-1",
"O15530-1",
"O15111-1",
"Q9Y4K3-1",
"O14920-1",
"Q9UDY8-1"
],
"evidence": [
{
"id": "R-HSA-202500",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-202500"
}
]
},
{
"id": "R-HSA-202534",
"name": "Ubiquitination of NEMO by TRAF6",
"equation": "",
"summary": "During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009).",
"cellular_location": "plasma membrane",
"input_participant_list": [],
"output_participant_list": [
"R-HSA-202562"
],
"enzyme_list": [
"O15530-1",
"O15111-1",
"Q9Y4K3-1",
"O14920-1",
"Q9UDY8-1",
"P61088-1"
],
"evidence": [
{
"id": "R-HSA-202534",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-202534"
}
]
},
{
"id": "R-HSA-202541",
"name": "p-S177,S181-IKKB:IKKA:pUb-NEMO phosphorylates IkB-alpha:NF-kB",
"equation": "",
"summary": "NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal (NLS) of NF-kB and prevent its nuclear translocation. A key event in NF-kB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta) by IKK. The phosphorylated IkB-alpha is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kB dimer p50/p65 into the nucleus to turn on target genes. (Karin & Ben-Neriah 2000)",
"cellular_location": "plasma membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-202541",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-202541"
}
]
},
{
"id": "R-HSA-2400001",
"name": "AKT1 E17K mutant phosphorylates CHUK (IKKalpha)",
"equation": "",
"summary": "AKT1 E17K gain-of-function mutant is expected to phosphorylate CHUK (IKKalpha), like the wild-type AKT (Ozes et al. 1999), but this has not been experimentally tested.",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [
"R-HSA-198615"
],
"enzyme_list": [
"P31749-1",
"O15111-1"
],
"evidence": [
{
"id": "R-HSA-2400001",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2400001"
}
]
},
{
"id": "R-HSA-2730876",
"name": "Phosphorylation of IKK-beta by TAK1",
"equation": "",
"summary": "In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex.
IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.",
"cellular_location": "cytosol, plasma membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O43318-1",
"O15111-1",
"Q9Y4K3-1",
"O14920-1",
"Q9UDY8-1",
"Q04759-1"
],
"evidence": [
{
"id": "R-HSA-2730876",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-2730876"
}
]
},
{
"id": "R-HSA-451561",
"name": "NEMO binds polyubiquitinated IRAK1",
"equation": "",
"summary": "NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008).",
"cellular_location": "cytosol, plasma membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1",
"P51617-1"
],
"evidence": [
{
"id": "R-HSA-451561",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-451561"
}
]
},
{
"id": "R-HSA-5228811",
"name": "NFKBIA variant is not phosphorylated within IkBA:NF-kappaB",
"equation": "",
"summary": "Several patients with ectodermal dysplasia with immunodeficiency (EDA-ID) were found to carry mutations in NFKBIA gene, which encodes inhibitor of NFkB alpha (IKBA, IkB alpha or NFKBIA) (Courtois G et al. 2003; MacDonald DR et al. 2007; Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Ohnidi). All human NFKBIA mutations are heterozygous gain-of-function (GoF) mutations that augment NFkB inhibition, causing autosomal dominant disease (Courtois G et al. 2003; Schimke LF et al. 2013; Zhang Q et al. 2016). NFKBIA mutations are either substitutions (S32I or M37K) affecting the phosphorylation of residues Ser32 and Ser36 or nonsense mutations (W11TER or E14TER) (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Zhang Q et al. 2016). The nonsense mutations in NFKBIA gene causing premature termination codons at positions 9 (Q9TER), 11 (W11TER), or 14 (E14TER) lead to translation reinitiation at an in-frame M37 downstream of the nonsense mutations resulting in the N-terminally truncated variant (NFKBIA F2_M37del) that lacks the critical phosphorylation sites at Ser32 or Ser36 (Lopes-Granados E et al. 2008; Schimke LF et al. 2013; Ohnishi H et al. 2012).The NFKBIA (IkBa) protein variants are expressed but cannot undergo phosphorylation-driven degradation. Disregarding induction signals, they remain constitutively bound to NFkB dimer and freeze the pathway sequestering NFkB dimers in the cytoplasm (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013). This has been verified by overexpressing mutant NFKBIA proteins encoded by patient alleles and showing that they override the wild-type protein and block NFkB-induced gene expression (Courtois G et al., 2003). NFkB signaling can be variably impaired in patients with IKBA-deficiency ranging from severe dominant-negative effect of NFKBIA S32I variant comparing to NFKBIA W11TER which results in functional NFkB haploinsufficiency (Lopes-Granados E et al. 2008; McDonald DR et al, 2007).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-5228811",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5228811"
}
]
},
{
"id": "R-HSA-5228840",
"name": "Defective IKBKB (IKK2) does not form a complex with IKBKA and IKBKG",
"equation": "",
"summary": "I kappa B kinase B (IKBKB or IKK beta) is the catalytic subunit of the IKK complex, which also contains kinase IKK1 (IKBKA/IKKalpha) and a regulatory subunit NEMO (IKBKG/IKKgamma). The IKK complex phosphorylates inhibitors of NFkB (IkB) in response to multiple stimuli. The phosphorylation of the IkB proteins triggers their polyubiquitination and subsequent degradation by the 26S proteasome. Free NFkB dimer translocates to the nucleus where it regulates the expression of target genes. Defects in NFkB signaling can affect both innate and adaptive immune-receptor pathways.
Homozygous duplication c.1292dupG in exon 13 of the IKBKB gene results in loss of expression of IKBKB (IKK beta). This mutation was identified in several patients diagnosed with severe combined immunodeficiency (SCID), a rare, potentially fatal, inherited disorderss associated with lack of mature B- and T-lymphocytes (Pannicke U et al. 2013). Patient-derived fibroblasts showed impaired NFkB-mediated responses upon stimulation with toll like receptor (TLR) ligands such as flagellin and lipopolysaccharide (LPS). Degradation of IkB alpha was absent upon TLR5 stimulation by flagellin. In addition, IL6 production was reduced in response to flagellin or lipopolysaccharide (which is specifically recognized by TLR4) (Pannicke U et al. 2013). Patient-derived B cells produced no immunoglobulins upon stimulation with TLR9 antagonist CpG (Pannicke U et al. 2013).", "cellular_location": "cytosol", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "O15111-1", "O14920-1" ], "evidence": [ { "id": "R-HSA-5228840", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5228840" } ] }, { "id": "R-HSA-5262921", "name": "Defective IKBKG (NEMO) destabilizes the association of IKBKA:IKBKB:IKBKG (via TLR)", "equation": "", "summary": "A group of hypomorphic IKBKG (NEMO) mutations has been associated with X-linked ectodermal dysplasia with immunodeficiency disorder (EDA-ID) (D\u00f6ffinger R et al. 2001; Fusco F et al. 2004; Hanson EP et al. 2008).
The IKBKG molecule consists of several structural domains. The N-terminal containing a large coiled-coil motif (CC1) is responsible for the interaction with IKK kinases (Marienfeld RB et al. 2006; Rushe M et al. 2008). The C-terminal domain is composed of a coiled-coil motif (CC2, aa 251-285)3, a leucine zipper (LZ; aa 301-337), and a zinc finger motif (ZF; aa 390-410). The C-terminal domain accounts for the oligomerization and binding to Lys-63-linked polyubiquitin chains (Agou F et al. 2004; Laplantine E et al. 2009; Ngadjeua F et al. 2013). This module shows a set of selected EDA-ID associated IKBKG mutations found across the coding gene range, that have been functionally tested in response to known toll like receptors (TLR) agonists. A mutation in the N-terminal domain, required for IKK assembly, reduced but did not abolish NF-kappaB activation following lipopolysaccharide stimulation (Fusco F et al. 2004). Mutations that disrupt the C-terminal domain, required for the recruitment of upstream factors, showed lower or no NF-kappaB activation (Fusco F et al. 2004; Cordier F et al. 2008)
NEMO-deficient human 3T8 Jurkat T cell line reconstituted with a construct of missense IKBKG variant L153R or C417R showed reduced NBkB activation in response to flagellin (TLR5 agonist) (Hanson EP et al. 2008). In addition, a C417R mutation located in ZF of IKBKG abolished both LPS- and TNF-induced phosphorylation of the activation loop of IKBKB (Yang F et al. 2004). The other EDA-ID associated missense mutation in ZF, IKBKG D406V, was also found to reduce NFkB activation upon stimulation of Jurkat T cell with IL-1beta, but did not alter the ZF structure as judged by fluorescence spectroscopy and metal binding colorimetric assay (Ngadjeua F et al. 2013). Moreover, dendritic cells from patients with EDA-ID caused by a C-terminal E391* deletion of the zinc finger of NEMO and by missense mutation C417R exhibit impaired MAPK activation in response to lipopolysaccharide (TLR4 agonist)(Ma CA et al. 2011). LPS-stimulated whole blood cells derived from patient with IKBKG R173G showed reduced NFkB activation (Ku CL et al. 2007). Furthermore, TLR-mediated TNF production was validated first in peripheral blood mononuclear cells (PBMC) from healthy donors and then evaluated in PBMC from 3 IKBKG-deficient patients bearing two missense (L153A and C417Y) and one nonsense (c.1056-1118del) mutations (Deering RP and Orange JS 2006). Mean TNF responses were significantly impaired across almost all TLR ligands tested, with the exception of c.1056-1118del variant in response to TLR9 agonist, which produced means within the control donor normative range (Deering RP and Orange JS 2006). Several experimental studies on the molecular basis for the observed functional defects suggest that IKBKG deficiency causes alteration in the assembly of IKK complex due to IKBKG oligomer instability (Fusco et al. 2004; Doffinger et al. 2001; Vinolo et al. 2006). A pathogenic mutation in the ZF domain of IKBKG was also reported to affect the interaction with Lys-63 and Met-1-linked di-ubiquitin, which correlates with its ubiquitin binding defect in vivo (Ngadjeua F et al. 2013).", "cellular_location": "cytosol", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "O15111-1", "O14920-1" ], "evidence": [ { "id": "R-HSA-5262921", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5262921" } ] }, { "id": "R-HSA-5357776", "name": "TNF:TNFR1:TRADD:TRAF2:K63polyUb-RIPK1:BIRC2,3:LUBAC recruits IKKA:IKBKB:IKBKG", "equation": "", "summary": "K63-polyubiquitinated RIPK1 binds to IKBKG (NEMO), resulting in the recruitment of the IKK complex to the TNF-alpha receptor 1 (TNFR1) signaling complex (Ea CK et al. 2006).
In addition, the linear polyubiquitination has been implicated in the NF-kappa-B activation. The linear ubiquitin chain assembly complex (LUBAC) ligase consisting of HOIL-1L, HOIP, and SHARPIN, specifically generates linear polyubiquitin chains (Kirisako T et al. 2006; Walczak H et al. 2012). IKBKG (NEMO), a regulatory component of the I\u03baB kinase (IKK) complex, is a substrate of LUBAC. LUBAC-mediated IKBKG ubiquitination enhances IKBKG interaction with the TNFR1 complex and stabilizes this protein complex to promote activation of NF-kappa-B (Haas TL et al. 2009).
Structural analysis revealed that NPL4 zinc finger 1 (NZF1) of HOIP can simultaneously bind both leucine zipper domains of NEMO (IKBKG) and ubiquitin and that both interactions are involved in the TNF alpha-mediated NF-kappa-B activation (Fujita H et al. 2014). In addition, NEMO (IKBKG) ubiquitination required RING-between-RING (RBR) domain of HOIL-1L (Smit JJ et al. 2013)",
"cellular_location": "cytosol, plasma membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q96EP0-1",
"Q9BYM8-1",
"Q5VV17-1",
"Q12933-1",
"Q13107-1",
"O75604-1",
"O15111-1",
"P98170-1",
"Q13546-1",
"P21580-1",
"O14920-1",
"Q13490-1",
"Q13489-1",
"Q6GQQ9-1",
"Q9NQC7-1",
"Q9UK80-1"
],
"evidence": [
{
"id": "R-HSA-5357776",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5357776"
}
]
},
{
"id": "R-HSA-5357831",
"name": "CHUK, IKBKB phosphorylate CYLD at S418",
"equation": "",
"summary": "CYLD is a deubiquitinating enzyme (DUB) that removes K63-linked ubiquitin chains from a large number of key signaling molecules, including tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and RIPK1. CYLD knockdown in human embryonic kidney 293 cells and human cervical carcinoma HeLa cells resulted in constitutive ubiquitination of TRAF2 (Reiley W et al. 2005) At the same time stimuli-induced TRAF2 ubiquitination was associated with site-specific phosphorylation of CYLD, a molecular event that was shown to inhibit CYLD-mediated deubquitination of TRAF2 (Reiley W et al. 2005; Hutti JE et al. 2009). Phosphorylation of CYLD was detected in TNF-alpha-stimulated HEK293T and HeLa cells, in LPS-treated BJAB cells, a human B\u2011cell line, and in human Jurkat T cells after stimulation with mitogens (Reiley W et al. 2005). Phoshorylation of CYLD was found to depend on IKKgamma (IKBKG), since it was blocked in IKBKG-deficient Jurkat T cells (Reiley W et al. 2005). Transfection and in vitro kinase assays reveal that both IKKalpha (CHUK) and IKKbeta (IKBKB) are able to phosphorylate CYLD (Reiley W et al. 2005). The noncanonical IKK family member IKKepsilon (IKBKE) was also reported to phosphorylate CYLD at serine 418 inhibiting CYLD deubiquitinase activity. The phosphorylation of CYLD by IKKepsilon is thought to contribute to IKKepsilon-driven cell transformation (Hutti JE et al. 2009).",
"cellular_location": "cytosol",
"input_participant_list": [
"R-HSA-741420"
],
"output_participant_list": [
"R-HSA-5212667"
],
"enzyme_list": [
"O15111-1",
"O14920-1",
"Q9NQC7-1"
],
"evidence": [
{
"id": "R-HSA-5357831",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5357831"
}
]
},
{
"id": "R-HSA-5607720",
"name": "p100:RELB binds active NIK:p-IKKA dimer",
"equation": "",
"summary": "NFKB2 (also known as p100) is a member of the NF-kB family of transcription factors. It is synthesised as large precursor with an N-terminal RHD (Rel homology domain) and a C-terminal series of ankyrin repeats that masks the nuclear localization signal of NFKB2/p100 localising it to the cytosol. In resting cells, p100 is associated with RELB (Transcription factor RelB) in the cytosol. Upon cell stimulation, the IkB-like C terminus of p100 is proteolyzed, resulting in RELB-p52 dimers that translocate to the nucleus (Senftleben et al. 2001, Hayden & Ghosh 2004). IKKA (I kappa-B kinase alpha) does not associate directly with p100 but in the presence of NIK (NF-kB-inducing kinase), IKKA stably binds to p100. Serine residues 866 and 870 of p100 are essential for the recruitment of IKKA to p100 by NIK. This interaction is required for p100 phosphorylation and subsequent processing by IKKA (Xiao et al. 2001, 2004).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q99558-1"
],
"evidence": [
{
"id": "R-HSA-5607720",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5607720"
}
]
},
{
"id": "R-HSA-5607722",
"name": "Active NIK phosphorylates IKKA dimer",
"equation": "",
"summary": "Accumulated NF-kB-inducing kinase (NIK) activates I kappa-B kinase alpha (IKKA) by directly phosphorylating the Ser176 and Ser180 with in the activation loop of IKKA. This phoshorylation is required for IKKA activity (Ling et al. 1998). Besides activating IKKA, NIK also serves as a docking molecule recruiting IKKA to p100 (Xiao et al. 2004).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q99558-1"
],
"evidence": [
{
"id": "R-HSA-5607722",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5607722"
}
]
},
{
"id": "R-HSA-5607723",
"name": "SCF-beta-TRCP binds p-7S-p100 in active NIK:p-S176,180-IKKA dimer:p-7S-p100:RELB",
"equation": "",
"summary": "Phosphorylated C-terminal serines 866, 870 and 872 in NFKB2 creates binding site for beta-TRCP (beta-transducin repeat-containing protein), the receptor subunit of a SCF-type of E3 ubiquitin ligase, SCF beta-TRCP (Liang et al. 2006). The SKP1-CUL1-F-box (SCF) ubiquitin E3 ligase superfamily is the largest family of cullin-RING ligases, with interchangeable F-box proteins orchestrating the trafficking proteins for ubiquitination and degradation (Weathington & Mallampalli 2013). Beta-TRCP is an F-box protein that contains two domains, an F-box motif that binds SKP1 and allows assembly into SKP1-CUL1 complexes and a second protein-protein interaction domain that interacts with phosphorylated serines in NFKB2 (Bai et al. 1996, Skowyra et al. 1997, Patton et al. 1998).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q99558-1"
],
"evidence": [
{
"id": "R-HSA-5607723",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5607723"
}
]
},
{
"id": "R-HSA-5607725",
"name": "SCF-beta-TRCP ubiquitinates p-7S-p100:RELB in active NIK:p-176,S180-IKKA dimer:p-7S-p100:SCF-beta-TRCP",
"equation": "",
"summary": "Ubiquitination of p100 is very specific. Lysine residue K855 has been identified as the anchoring site for ubiquitin and required for signaling mediated processing of p100 to p52. In the presence of SCF-beta-TRCP E3 ligase the ubiquitin (Ub) conjugated to E2 (E2-Ub thioester) is attached to p100 at K855 (Amir et al. 2004). Several rounds of ubiquitin conjugation can produce long chains of ubiquitin moieties (polyubiquitylation), the first of which is covalently bound to p100. At this point the polyubiquitylated p100 is committed to association with, and unfolding and processing by, the 26S proteasome (Pickart & Cohen 2004).
Efficient ubiquitination of phosphorylated p100 by SCF-beta-TRCP E3 ligase also requires the presence of the components of the NEDD8 pathway: UBA3 (NEDD8-activating enzyme E1 catalytic subunit), UBC12 (NEDD8-conjugating enzyme Ubc12 (E2)), NEDD8 (Neural precursor cell expressed developmentally down-regulated protein 8). NEDD8 binds and promotes a conformational change in CUL1 that may result in efficient formation of an E2-E3 complex, thus stimulating SCF complexes activity (Kawakami et al. 2001, Morimoto et al. 2000, Read et al. 2000).",
"cellular_location": "cytosol",
"input_participant_list": [
"R-HSA-4419894",
"R-HSA-947632"
],
"output_participant_list": [
"R-HSA-4419894"
],
"enzyme_list": [
"P61081-1",
"O15111-1",
"Q99558-1",
"Q8TBC4-1"
],
"evidence": [
{
"id": "R-HSA-5607725",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5607725"
}
]
},
{
"id": "R-HSA-5607726",
"name": "Active NIK:p-S176,180-IKKA dimer phosphorylates p100:RELB",
"equation": "",
"summary": "After being recruited into the NIK (NFkB-inducing kinase) complex, activated IKKA (I kappaB kinase alpha) phosphorylates serine residues 99, 108, 115, 123, 866, 870 and 872 located in both N- and C-terminal regions of NFKB2/p100. The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100. The C-terminal serine residues create a binding site for beta-TRCP (beta-transducinrepeat-containing protein), a ubiquitin E3 ligase (Xiao et al. 2001 & 2004, Liang et al. 2006).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q99558-1"
],
"evidence": [
{
"id": "R-HSA-5607726",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5607726"
}
]
},
{
"id": "R-HSA-5607742",
"name": "K63polyUb-p-3T,1S-TAK1 phosphorylates IKK-beta",
"equation": "",
"summary": "In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex.
IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.",
"cellular_location": "cytosol, plasma membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O43318-1",
"O15111-1",
"Q9Y4K3-1",
"O14920-1",
"Q9UDY8-1"
],
"evidence": [
{
"id": "R-HSA-5607742",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5607742"
}
]
},
{
"id": "R-HSA-5609665",
"name": "CHUK, IKBKB and IKBKG form IKK complex",
"equation": "",
"summary": "The multimeric I kappa B kinase (IKK) complex is a key regulator of NF-kappa-B signaling, which is responsible for the phosphorylation of inhibitor kB (IkB). The phosphorylation by IKK triggers K48-linked ubiquitination of IkB leading to proteasomal degradation of IkB, allowing translocation of NFkB factor to the nucleus, where it can activate transcription of a variety of genes participating in the immune and inflammatory response, cell adhesion, growth control, and protection against apoptosis (Alkalay I et al. 1995; Collins T et al. 1995; Kaltschmidt B et al. 2000; Oeckinghaus A and Ghosh S 2009). The IKK complex is composed of the two catalytic subunits, IKKa (IKBKA, IKK1 or CHUK) and IKKb (IKK2 or IKBKB) kinases, and a regulatory subunit, NF-kappa-B essential modulator (NEMO, IKKg or IKBKG). IKBKG (NEMO) associates with the C-termini of unphosphorylated IKKs and promotes the IKK complex activation (Rothwarf DM et al. 1998). The molecular composition and stoichiometry of the IKK complex remains debatable, although the core IKK complex that range from 700 to 900 kDa is thought to consist of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies (DiDonato JA et al. 1997; May J et al. 2002; Tegethoff S et al. 2003; Marienfeld RB et al. 2006; Rushe M et al. 2008).",
"cellular_location": "cytosol",
"input_participant_list": [
"R-HSA-168104",
"R-HSA-168108",
"R-HSA-168114"
],
"output_participant_list": [
"R-HSA-168113"
],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-5609665",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5609665"
}
]
},
{
"id": "R-HSA-5626962",
"name": "GNB2L1 binds IKKA:IKKB:NEMO",
"equation": "",
"summary": "Guanine nucleotide-binding protein subunit beta-2-like 1 (GNB2L1) also known as receptor of activated protein kinase C 1 (RACK1) is reported to associate with the IKK complex in a TNF-triggered manner (Yao F et al. 2014). This interaction interfered with TRAF2-mediated recruitment and the subsequent phosphorylation of IKK triggered by TNF. By modulating the interaction between TRAF2 and the IKK complex, GNB2L1 (RACK1) regulated the level of NFkB activation in response to TNF (Yao F et al. 2014).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-5626962",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5626962"
}
]
},
{
"id": "R-HSA-5684267",
"name": "IKBKB phosphorylates NFkB p105 within the NFkB p105:TPL2:ABIN2 complex",
"equation": "",
"summary": "NFkappaB p105 protein (p105) is a precursor of the NFkappaB p50 subunit and an inhibitor of NFkappaB. The IkappaB kinase (IKK) complex phosphorylates p105 on S927 within the PEST region. TNF-alpha-induced p105 proteolysis additionally requires the phosphorylation of S932. Purified IKK (IKK1) or IKKB (IKK2) can phosphorylate both these regulatory serines in vitro.",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1",
"P41279-1"
],
"evidence": [
{
"id": "R-HSA-5684267",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5684267"
}
]
},
{
"id": "R-HSA-5684275",
"name": "IKBKB phosphorylates TPL2 (MAP3K8) at Ser400",
"equation": "",
"summary": "The activity of tumor progression locus-2 (TPL2, also known as COT and MAP3K8) is regulated by means of phosphorylation. MAP3K8 undergoes phosphorylated on S400 in its C-terminal tail to activate MAP2Ks (MEK1/2) following LPS stimulation of macrophages. Different experimental systems have suggested that S400 is either autophosphosphorylated by MAPK3P8 (IL-1?-stimulated IL-1R-293T cells) or transphosphorylated by an unknown kinase (LPS-stimulated RAW264.7 macrophages).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1",
"P41279-1"
],
"evidence": [
{
"id": "R-HSA-5684275",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5684275"
}
]
},
{
"id": "R-HSA-8863895",
"name": "IKKB phosphorylates SNAP23",
"equation": "",
"summary": "A major reserve of MHC-I in dendritic cells reside within the endocytic recycling compartments (ERC). MHC-I trafficking to the ERC is regulated by the activity of Rab11a and subsequent trafficking from ERC to phagosomes is controlled by TLR-MyD88-IKK2-dependent phosphorylation of phagosomal SNAP23. Toll-like receptor (TLR) signalling regulate cross-presentation as they regulate phagocytosis and phagolysosomal fusion (Nair et al. 2011). MHC-I bearing ERC are enriched with R-SNAREs like RAB11a, VAMP3, and VAMP8. These SNARE molecules can interact with Q-SNARE SNAP23 present on phagosomes and this mediates membrane fusion. This interaction of SNAP23 with R-SNAREs require phosphorylation of SNAP23 (on Ser-95) by IKK2, and IKK2 is activated by TLR signalling. SNAP23 phosphorylation may increase SNAP23 binding to SNAREs. It may also regulate platelet and mast cell secretion (Karim et al. 2013, Suziki & Verma 2008).",
"cellular_location": "cytosol, phagocytic vesicle membrane",
"input_participant_list": [
"R-HSA-8863966"
],
"output_participant_list": [
"R-HSA-8863923"
],
"enzyme_list": [
"Q06187-1",
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-8863895",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-8863895"
}
]
},
{
"id": "R-HSA-9014343",
"name": "IKBKG subunit of IKK complex binds K63pUb- RIP1 within the TLR3 complex",
"equation": "",
"summary": "Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation.",
"cellular_location": "cytosol, endosome membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q13546-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9014343",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9014343"
}
]
},
{
"id": "R-HSA-933530",
"name": "Activation of IKK by MEKK1",
"equation": "",
"summary": "In Human, IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex and NFkB mediated antiviral responce are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO.[Solt et al 2009]; [Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it's remained unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.
This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.
IKK beta is the major IKK catalytic subunit for NF-kB activation. MEKK1 can activate both IKK-alpha (IKKA) and IKK-beta (IKKB) in vivo. MEKK1 phosphorylates Ser-176 and Ser-180 in IKKA and Ser-177 and Ser-181 in IKKB activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.",
"cellular_location": "cytosol, mitochondrial outer membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q12933-1",
"O15111-1",
"Q13233-1",
"Q9Y4K3-1",
"Q8IUD6-1",
"Q9BYX4-1",
"O14920-1",
"Q14258-1",
"O95786-1",
"Q9C037-1"
],
"evidence": [
{
"id": "R-HSA-933530",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-933530"
}
]
},
{
"id": "R-HSA-933539",
"name": "Recruitment of IKK complex",
"equation": "",
"summary": "The molecular mechanisms by which caspase-8/10 attribute to NF-kB signaling is unclear. Caspase-8 might act as a scaffolding protein by bringing the IKK-complex in close proximity to its activator TAK1. The prodomain of Caspase-8 could interact with IKK2 in the IKK complex whereas the protease homology domain failed to do so. These results indicate that the interaction of the DEDs-containing prodomain of caspase-8 with the IKKs may be crucial for the NF-kB induction by caspase-8.",
"cellular_location": "cytosol, mitochondrial outer membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q14790-1",
"O15111-1",
"Q13546-1",
"Q92851-1",
"Q8IUD6-1",
"Q9BYX4-1",
"O14920-1",
"Q14258-1",
"O95786-1",
"Q9C037-1"
],
"evidence": [
{
"id": "R-HSA-933539",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-933539"
}
]
},
{
"id": "R-HSA-937029",
"name": "IKBKG subunit of IKK complex binds polyubiquinated RIP1",
"equation": "",
"summary": "Structural studies showed that NEMO binds both Lys-63- and linear polyubiquitin chains,both critical for NF-kB activation.",
"cellular_location": "cytosol, endosome membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q13546-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-937029",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-937029"
}
]
},
{
"id": "R-HSA-937032",
"name": "NEMO subunit of IKK complex binds to activated IRAK1",
"equation": "",
"summary": "NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q9Y4K3-1",
"O14920-1",
"P51617-1"
],
"evidence": [
{
"id": "R-HSA-937032",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-937032"
}
]
},
{
"id": "R-HSA-9749471",
"name": "NLRX1 binds CHUK:IKBKB:IKBKG",
"equation": "",
"summary": "Nucleotide binding oligomerization domain (NOD)-like receptor (NLR) family member X1 (NLRX1) has been implicated in regulation of the Toll-like receptor (TLR)-mediated nuclear factor kappa-B (NF-kappa-B) signaling pathway. NLRX1 deficiency enhanced phosphorylation of catalytic subunits (CHUK and IKBKB) of the IkB kinase (IKK) complex and NF-kappa-B activation and led to elevated production of inflammatory cytokines in mouse cells in response to bacterial lipopolysaccharide (LPS, a TLR4 ligand) (Allen IC et al. 2011; Xia X et al. 2011; Ma D et al. 2019). NLRX1-knockdown mice showed enhanced susceptibility to LPS-induced septic shock thus further confirming that NLRX1 functions as a negative regulator of TLR signaling in vivo (Xia X et al. 2011). NLRX1 was shown to interact with TRAF6 (Allen et al. 2011; Xia X et al. 2011) and the IKK complex (CHUK:IKBKB:IKBKG) (Xia X et al. 2011) in human and mouse cells. Specifically, in unstimulated cells, NLRX1 was shown to associate with TRAF6 (Xia X et al. 2011). Upon stimulation with LPS, NLRX1 is thought to undergo K63-linked polyubiquitination. Although TRAF6 possesses E3 ubiquitin ligase activity, the TRAF6 deficiency did not affect NLRX1 ubiquitination in mouse embryonic fibroblast (MEF) (Xia X et al. 2011). Further studies are required to identify E3 ubiquitin ligase which is responsible for the ubiquitination of NLRX1. Ubiquitinated NLRX1 then binds to the IKK complex, blocking phosphorylation of the catalytic subunits CHUK (IKBKA) and IKBKB (Xia X et al. 2011). Mutagenesis studies showed that the C-terminal leucine-rich repeat (LRR) domain of NLRX1 binds to the kinase domain of IKBKB (Xia X et al. 2011).
The regulatory effects of NLRX1 are highly cell type specific (reviewed in Fekete T et al. 2021). As a regulator of inflammation, NLRX1 has been implicated in the pathology of diverse diseases (reviewed in Pickering RJ & Booty LM 2021).
This Reactome event shows interaction between NLRX1 and the IKK complex.",
"cellular_location": "cytosol, endoplasmic reticulum membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9749471",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9749471"
}
]
},
{
"id": "R-HSA-9749494",
"name": "IKBIP binds IKBKB and CHUK",
"equation": "",
"summary": "The I-kappa-B-kinase (IKK) complex consists of two catalytic subunits, IKBKA (KK\u03b1 or CHUK) and IKBKB (IKK\u03b2), associated with a regulatory subunit IKBKG (NEMO). Yeast two-hybrid screening identified inhibitor of nuclear factor kappa-B kinase-interacting protein (IKBIP or IKIP) as an IKBKB-binding protein (Hofer-Warbinek R et al. 2004). IKBIP was found to downregulate NF-kappa-B activation and induction of proinflammatory cytokines in human and mouse myeloid cells in response to Toll-like receptor (TLR) ligands (Wu H et al. 2020). In addition, IKBIP deficiency resulted in prolonged phosphorylation of IKBKB, CHUK and p65, and increased expression of NF-kappaB-responsive genes in myeloid cells after stimulation with LPS, TNF-\u03b1, and IL-1\u03b2. Moreover, IKBIP co-immunoprecipitated with IKBKA (CHUK) and IKBKB subunits, but not with IKBKG, upon co-expression of tagged proteins in human embryonic kidney HEK293T cells (Wu H et al. 2020). Mutagenesis analysis revealed that the N-terminal region of IKBIP interacts with leucine zipper (LZ) and helix-loop-helix (HLH) domains of IKBKB. Confocal microscopy showed that IKBKB colocalizes with IKBIP in the endoplasmic reticulum (ER) upon co-expression of tagged proteins in Hela cells (Wu H et al. 2020). These data suggest that IKBIP negatively regulates NF-kappa-B activation via targeting IKBKB and CHUK and inhibiting their phosphorylation (Wu H et al. 2020).",
"cellular_location": "cytosol, endoplasmic reticulum membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9749494",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9749494"
}
]
},
{
"id": "R-HSA-9749505",
"name": "LRRC14 binds IKBKB and CHUK",
"equation": "",
"summary": "Leucine-rich repeat-containing protein 14 (LRRC14) binds to the helix-loop-helix (HLH) domain of IKBKB (Wu C et al. 2016). This binding blocks IKBKB interaction with IKBKG (NEMO) disrupting I\u03baB kinase (IKK) complex formation and NF-kappa-B activation (Wu C et al. 2016).",
"cellular_location": "cytosol, endoplasmic reticulum membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9749505",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9749505"
}
]
},
{
"id": "R-HSA-9750226",
"name": "NLRC5 binds IKBKB and CHUK",
"equation": "",
"summary": "The I-kappa-B-kinase (IKK) complex, a key regulator of the nuclear factor kappa B (NF-kB) signaling pathway, consists of two catalytic subunits, IKBKA (KK\u03b1 or CHUK) and IKBKB (IKK\u03b2), associated with a regulatory subunit IKBKG (NEMO). The IKK complex is responsible for the phosphorylation of inhibitors of NF-kB (IkBs), such as NFKBIA or NFKBIB. Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing the transcription factor NF-kB thereby allowing translocation of NF-kB to the nucleus to regulate gene expression (Oeckinghaus A and Ghosh S 2009). NOD-like receptor C5 (NLRC5), the transcriptional activator of genes coding for MHC-I, has been implicated in the regulation of inflammatory pathways and IFN-dependent antiviral defense (Benko S et al. 2010; Cui J et al. 2010). Overexpression of NLRC5 inhibited NFkB-luciferase reporter activity in human embryonic kidney 293T (HEK293T) cells treated with interleukin (IL)-1\u03b2, TNF-\u03b1 or toll-like receptor (TLR) agonists such as bacterial LPS (TLR4 ligand) or R848 (TLR7/8 ligand) (Cui J et al. 2010). Similar findings were obtained with human monocytic THP-1 cells and murine embryonic fibroblasts (MEFs) (Cui J et al. 2010). Further, NLRC5 deficiency resulted in enhanced phosphorylation of IKBKB, CHUK, and increased expression of NF-kB-responsive cytokines (such as TNF-\u03b1 and IL-6), in LPS-stimulated THP-1 and mouse macrophage RAW264.7 cells (Cui J et al. 2010). NLRC5 deficiency enhanced NF\u2010kB activation in mouse cells in response to TLR3, TLR4, TLR7, TLR9 ligands (Tong Y et al. 2012) and TLR2 ligand (Wang M et al. 2019). Knockdown of NLRC5 also enhanced cytokine response and antiviral immunity in vesicular stomatitis virus (VSV)-treated primary human monocytes, primary murine macrophages and RAW264.7 cells. Studies with NLRC5-deficient mice confirmed the regulatory role of NLRC5 in the induction of NF-kB and type I interferon in response to LPS or VSV infection (Tong Y et al. 2012). Moreover, NLRC5 co-immunoprecipitated with IKBKA (CHUK) and IKBKB subunits, but not with IKBKG, upon co-expression of tagged proteins in HEK293T cells (Cui J et al. 2010). Mutagenesis analysis revealed that human NLRC5 targets the amino-terminal kinase domain (KD) of IKBKB. Fractionation of RAW264.7 cells extracts on a size-exclusion column followed by immunoblotting analysis showed that both CHUK:IKBKB:IKBKG and CHUK:IKBKB:NLRC5 complexes co-exist in unstimulated cells suggesting that NLRC5 inhibits the interaction between IKBKG (NEMO) and IKBKB/CHUK (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK upon stimulation is regulated by TRAF2/TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). These data suggest that NLRC5 negatively regulates NF-kappa-B activation via targeting IKBKB and CHUK.",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"P54578-1",
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9750226",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9750226"
}
]
},
{
"id": "R-HSA-9750946",
"name": "TRAF2,6 ubiquitinates NLRC5",
"equation": "",
"summary": "NOD-like receptor C5 (NLRC5) functions as negative regulator of the NF-kappa B signaling pathway by targeting the I-kappa-B-kinase (IKK) complex (Cui J et al. 2010). The IKK complex consists of two catalytic subunits, IKBKA (KK\u03b1 or CHUK) and IKBKB (IKK\u03b2), associated with a regulatory subunit IKBKG (NEMO). NLRC5 directly binds to CHUK and IKBKB inhibiting their phosphorylation and interaction with IKBKG (Cui J et al. 2010). The dynamics of NLRC5 interaction with IKBKB/CHUK is regulated by TRAF2 or TRAF6-dependent ubiquitination of NLRC5 (Meng Q et al. 2015). Active TRAF2/6 catalyzed K63-linked polyubiquitination of NLRC5 at K1178 in human and mouse cells in response to LPS stimulation. The ubiquitinated NLRC5 (K63-polyUb-NLRC5) blocked NLRC5 interaction with IKBKB/CHUK thereby resulting in a decreased inhibitory function of NLRC5. The TRAF2/TRAF6-mediated ubiquitination of NLRC5 was reversely regulated by USP14 (Meng Q et al. 2015).;",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"Q12933-1",
"O15111-1",
"Q9Y4K3-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9750946",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9750946"
}
]
},
{
"id": "R-HSA-975119",
"name": "NEMO subunit of IKK complex binds to activated IRAK1 upon stimulation of TLR7/8 or 9.",
"equation": "",
"summary": "NF-kappa-B essential modulator (NEMO, also known as IKKG abbreviated from Inhibitor of nuclear factor kappa-B kinase subunit gamma) is the regulatory subunit of the IKK complex which phosphorylates inhibitors of NF-kappa-B leading to dissociation of the inhibitor/NF-kappa-B complex. NEMO binds to K63-pUb chains (Ea et al. 2006; Wu et al. 2006), linking K63-pUb-hp-IRAK1 with the IKK complex. Models of IL-1R dependent activation of NF-kappaB suggest that the polyubiquitination of both TRAF6 and IRAK1 within a TRAF6:IRAK1 complex and their subsequent interactions with the TAK1 complex and IKK complex respectively brings these complexes into proximity, facilitating the TAK1-catalyzed activation of IKK (Moynagh, 2008).",
"cellular_location": "cytosol, endosome membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"Q9Y4K3-1",
"O14920-1",
"P51617-1"
],
"evidence": [
{
"id": "R-HSA-975119",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-975119"
}
]
},
{
"id": "R-HSA-9754839",
"name": "SARS-CoV-2 9b binds IKBKG",
"equation": "",
"summary": "The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) open reading frame 9b protein (ORF9b or 9b) localizes to the membrane of mitochondria to suppress host innate immunity downstream of the DDX58/IFIH1:MAVS signaling axis (Jiang HW et al. 2020; Gordon DE et al. 2020a; Wu J et al. 2021). Ectopic expression of viral 9b antagonized the antiviral type I IFN response during SARS-CoV-2 infection in primary human pulmonary alveolar epithelial cells (HPAEpiC) (Wu J et al. 2021). Similar findings were observed in infected human airway epithelium BEAS-2B and Calu-3 cells (Wu J et al. 2021). SARS-CoV-2 9b was found to target the nuclear factor \u03baappa B (NF-\u03baB) essential modulator (NEMO, also known as IKBKG). Co-immunoprecipitation assay identified interaction between 9b and IKBKG upon co-expression of tagged proteins in human embryonic kidney 293T (HEK293T) cells (Wu J et al. 2021). Further, overexpressed viral 9b co-localized with IKBKG in the cytoplasm of Sendai virus (SeV)-induced human lung adenocarcinoma NCI-H1299 cells. Mutagenesis revealed that the N-terminus of 9b mediates its interaction with IKBKG upon viral infection. The viral 9b protein inhibited the K63-linked ubiquitination of IKBKG in a dose-dependent manner upon co-expression of 9b, IKBKG and ubiquitin (Ub) in virally stimulated HEK293T (Wu J et al. 2021). These data suggest that the mitochondria-associated SARS-CoV-2 9b (ORF9b) protein binds IKBKG to disrupt the K63-linked polyubiquitination of IKBKG and the activation of the IKK complex (Wu J et al. 2021).
",
"cellular_location": "mitochondrial outer membrane",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9754839",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9754839"
}
]
},
{
"id": "R-HSA-9755734",
"name": "SARS-CoV-2 N binds IKBKB",
"equation": "",
"summary": "Viral RNA binding to SARS-CoV-2 nucleocapsid protein (N) induces liquid-liquid phase separation (LLPS) (Wu Y et al. 2021; Wang S et al. 2021; Cubuk J et al. 2021; Lu S et al. 2021). Viral N protein:RNA LLPS recruits TGF-beta-activated kinase 1 (TAK1) and I\u03baB kinase (IKK) complexes and enhances their interaction which in turn promotes NF-kappaB activation and expression of pro-inflammatory cytokines (Wu Y et al. 2021). The C-terminal domain (CTD) of viral N is essential for LLPS (Wu Y et al. 2021; Wang S et al. 2021) and induction of NF-kappaB signaling in mammalian cells (Wu Y et al. 2021). Deletion of CTD abolished SARS-CoV-2 N LLPS and the recruitment of TAK1/IKK complexes. Co-immunoprecipitation analysis revealed that SARS-CoV-2 N protein interacted with the components of the TAK1 complex and the IKK complex, including TAK1, TAB1, TAB2, IKBKA (CHUK), IKBKB, and NEMO (IKBKG) upon co-expression in human embryonic kidney 293T (HEK293T) cells (Wu Y et al. 2021). Endogenous IKK and TAK1 immunoprecipitated together with N in human lung cancer Calu3 cells infected with SARS-CoV-2. Immunofluorescence analysis further revealed the enhanced co-localization between N protein and IKBKB after SARS-CoV-2 infection in human hepatoma Huh7 cells. These data suggest that SARS-CoV-2 N:RNA LLPS serves as a platform to enhance the interaction between TAK1 and IKK complexes promoting NF-kappaB-dependent inflammatory responses (Wu Y et al. 2021).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9755734",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9755734"
}
]
},
{
"id": "R-HSA-9758604",
"name": "Ubiquitination of IKBKG by TRAF6",
"equation": "",
"summary": "During the phosphorylation of the IKK beta (IKBKB), the regulatory subunit NEMO (IKBKG) undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 acts as a E3 ligase and induces this ubiquitination. Studies of different NF-kappa-B signaling pathways revealed several potential ubiquitination sites on IKBKG (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009).",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O43318-1",
"Q96QP1-1",
"O15111-1",
"Q9Y4K3-1",
"O14920-1",
"P61088-1",
"Q9UMW8-1",
"P51617-1"
],
"evidence": [
{
"id": "R-HSA-9758604",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9758604"
}
]
},
{
"id": "R-HSA-9761344",
"name": "USP18 binds IKBKG within IKK complex",
"equation": "",
"summary": "Expression of ubiquitin-specific protease 18 (USP18) is induced by various Toll-like receptor (TLR) ligands in human monocytes and macrophages (Yang Z et al. 2015). A nuclear factor kappa B (NF-kappa-B, NF-\u03baB) luciferase reporter gene assay showed that expression of tagged USP18 negatively regulates TLR-mediated activation of NF-kappa B in human embryonic kidney HEK293T cells. USP18 also inhibited the degradation of endogenous I\u03baB\u03b1 protein in HEK293T cells (Yang Z et al. 2015). Further, knockdown of USP18 by USP18-specific small interfering RNAs (siRNA) enhanced NF-kappaB activity in LPS- stimulated human monocyte-like THP-1 cells (Yang Z et al. 2015). Co-immunoprecipitation and immunoblot analysis revealed that USP18 targets the regulatory subunit IKBKG (NEMO) of the IKK (CHUK:IKBKB:IKBKG) complex upon co-expression of tagged proteins in HEK293T cells. Mutagenesis analysis using HEK293T cells showed that USP18 directly binds to the UBAN motif of IKBKG inhibiting K63-linked ubiquitination of IKBKG by masking the ubiquitination sites at K325 and K326 (Yang Z et al. 2015). In addition, USP18 targets the TAK1-TAB1 complex and cleaves the K63-linked polyubiquitin chains of TAK1 in a protease-dependent manner (Liu X et al. 2013; Yang Z et al. 2015). These data suggest that USP18 functions as a negative regulator of NF-kappa-B activation.
This Reactome events shows USP18 binding to IKBKG within the IKK (CHUK:IKBKB:IKBKG) complex.", "cellular_location": "cytosol", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "O15111-1", "O14920-1", "Q9UMW8-1" ], "evidence": [ { "id": "R-HSA-9761344", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9761344" } ] }, { "id": "R-HSA-9773803", "name": "Active IKBKB phosphorylates NF-kappa-B inhibitor", "equation": "", "summary": "In human, IkBs (NFKBIA, NFKBIB or NFKBIE) are inhibitory proteins that sequesters NF-kappa-B in the cytoplasm by masking a nuclear localization signal, located just at the C-terminal end of the RelA (p65) subunit of the RelA:NFKB1 heterodimer.
A key event in NF-kappa-B activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kappa-B signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta (IKKb, IKBKB) in an IKK gamma (IKBKG, NEMO)-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human NFKBIA (IkB-alpha) or Ser19 and Ser22 of NFKBIB (IkB-beta)). Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kappa-B.
",
"cellular_location": "cytosol",
"input_participant_list": [],
"output_participant_list": [],
"enzyme_list": [
"O15111-1",
"O14920-1"
],
"evidence": [
{
"id": "R-HSA-9773803",
"database": "Reactome",
"url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9773803"
}
]
},
{
"id": "R-HSA-9818789",
"name": "CHUK, IKBKB phosphorylate RIPK1 at S25",
"equation": "",
"summary": "Binding of TNF\u03b1 to TNF receptor 1 (TNFR1) induces the sequential formation of several signaling complexes, namely complex I and complex IIa/b (Walczak H 2011; Yuan J et al. 2019). These complexes support either cell survival (complex I) or cell death (complex II). The dynamic assembly of these complexes is tightly regulated by proteolysis, ubiquitination and phosphorylation of receptor-interacting serine/threonine protein kinase 1 (RIPK1) and other components of the TNF\u03b1 signaling pathway (reviewed in Yuan J et al. 2019; Varfolomeev E & Vucic D 2022). RIPK1 functions as a key regulator of both cell survival and cell death (reviewed in Ju E et al. 2022). Enzymatically inactive polyubiquitin-bound RIPK1 serves as a scaffold in the TNFR1 signaling complex (complex I) to recruit TAK1 kinase complex and I-kappa-B kinase (IKK) complex contributing to activation of mitogen-activated protein kinase (MAPK) and NF-kappa-B signaling pathways, which regulate expression of pro-survival and inflammatory genes. Deubiquitination of RIPK1 leads to the activation of RIPK1 kinase activity, which promotes autophosphorylation of RIPK1 and RIPK1 kinase-dependent cell death (reviewed in Ju E et al. 2022). The kinase activity of RIPK1 is regulated by phosphorylation (Lafont E et al. 2018; Dondelinger Y et al. 2019; reviewed in Delanghe T et al. 2020; Ju E et al. 2022). The components of I-kappa-B kinase complex, namely inhibitor of nuclear factor kappa B subunit \u03b1 (IKK\u03b1 or CHUK) and subunit \u03b2 (IKK\u03b2 or IKBKB), can directly phosphorylate RIPK1 within the membrane-bound TNFR1 signaling complex (complex I) (Dondelinger Y et al. 2015, 2019). IKK phosphorylates S25 in the kinase domain of RIPK1 to block ATP binding, preventing RIPK1 kinase activation and cell death (Dondelinger Y et al. 2019). Expression of phospho-mimetic S25D RIPK1 mutant prevented TNF-induced cell death in RIPK1-null human Jurkat cells and mouse embryonic fibroblasts (MEF). Autophosphorylation of RIPK1 on S166 and activation of RIPK1 kinase were inhibited in mouse bone marrow-derived macrophages (BMDMs) and MEFs isolated from mice carrying S25D RIPK1 mutant (Dondelinger Y et al. 2019; Puylaert P et al. 2022). Inhibition of IKK activity by Yersinia infection or by SHARPIN gene mutations results in defective phosphorylation of RIPK1 at S25 by IKK\u03b1/\u03b2 (Dondelinger Y et al. 2019). Restoring S25 phosphorylation with S25D RIPK1 prevented TNF-induced RIPK1 kinase-dependent cell death in Yersinia-infected BMDMs. Further, mimicking S25 phosphorylation impaired host immune response to Yersinia infection in vivo in bone marrow chimeric mice, suggesting that RIPK1 kinase-dependent cell death contributes to immune defense in response to pathogens. Similarly, S25D RIPK1 suppressed TNF-induced cell death in mouse dermal fibroblasts (MDFs) isolated from SHARPIN-deficient mice. These data suggest that IKK\u03b1/\u03b2-mediated phosphorylation of RIPK1 at S25 downregulates RIPK1 auto-phosphorylation downstream of TNFR1, thereby preventing TNF\u03b1-induced RIPK1 kinase-dependent cell death (Dondelinger Y et al. 2019).
This Reactome event describes IKK mediated phosphorylation of RIPK1 at S25 within the TNFR1 signaling complex.; ; ;", "cellular_location": "cytosol, plasma membrane", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "Q96EP0-1", "Q9BYM8-1", "Q12933-1", "O15111-1", "P98170-1", "Q13546-1", "O14920-1", "Q13490-1", "Q13489-1", "Q9NQC7-1" ], "evidence": [ { "id": "R-HSA-9818789", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9818789" } ] }, { "id": "R-HSA-9836500", "name": "IKK complex is activated by PKR", "equation": "", "summary": "Protein kinase R (PKR, EIF2AK2), through its catalytic domain in the N-terminus, binds to the IKK complex, activating it by enhancing the autophosphorylation of IKBKB. It is unclear whether PKR itself needs to be in its activated form for this process. The activated IKK complex subsequently activates NFkappa-B by phosphorylating its inhibitors (Chu et al, 1999; Bonnet et al, 2000; Gil et al, 2001: Zamanian-Daryoush et al, 2000; Bonnett et al, 2006).", "cellular_location": "cytosol", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "O15111-1", "O14920-1", "P19525-1" ], "evidence": [ { "id": "R-HSA-9836500", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-9836500" } ] } ], "reaction_participants": [ { "participant_id": "R-HSA-168104", "participant_name": "CHUK [cytosol]", "crossref": [ { "id": "O15111", "database": "UniProt", "url": "" }, { "id": "HMDBP02038", "database": "HMDB Protein", "url": "" }, { "id": "IKKA_HUMAN", "database": "ZINC - FDA approved", "url": "" }, { "id": "ENSP00000359424", "database": "Ensembl", "url": "" }, { "id": "IKKA_HUMAN", "database": "ZINC - Substances", "url": "" }, { "id": "ENST00000370397", "database": "Ensembl", "url": "" }, { "id": "ENSG00000213341", "database": "Ensembl", "url": "" }, { "id": "IKKA_HUMAN", "database": "ZINC - Predictions - Purchasable", "url": "" }, { "id": "5TQW", "database": "PDB", "url": "" }, { "id": "IKKA_HUMAN", "database": "ZINC - World Drugs", "url": "" }, { "id": "ENSG00000213341-CHUK", "database": "HPA", "url": "" }, { "id": "5TQX", "database": "PDB", "url": "" }, { "id": "5TQY", "database": "PDB", "url": "" }, { "id": "ENSG00000213341", "database": "OpenTargets", "url": "" }, { "id": "O15111", "database": "PRO", "url": "" }, { "id": "3BRT", "database": "PDB", "url": "" }, { "id": "IKKA_HUMAN", "database": "ZINC - Investigational", "url": "" }, { "id": "5EBZ", "database": "PDB", "url": "" }, { "id": "IKKA_HUMAN", "database": "ZINC - Biogenic", "url": "" }, { "id": "NP_001269.3", "database": "RefSeq", "url": "" }, { "id": "O15111", "database": "GeneCards", "url": "" }, { "id": "24278", "database": "Orphanet", "url": "" }, { "id": "O15111", "database": "ZINC target", "url": "" }, { "id": "O15111", "database": "Pharos - Targets", "url": "" }, { "id": "1989", "database": "Guide to Pharmacology - Targets", "url": "" }, { "id": "2.7.11.10", "database": "IntEnz", "url": "" } ] }, { "participant_id": "R-HSA-168108", "participant_name": "IKBKG [cytosol]", "crossref": [ { "id": "Q9Y6K9", "database": "UniProt", "url": "" }, { "id": "3FX0", "database": "PDB", "url": "" }, { "id": "4BWN", "database": "PDB", "url": "" }, { "id": "NP_001093327.1", "database": "RefSeq", "url": "" }, { "id": "ENST00000618670", "database": "Ensembl", "url": "" }, { "id": "NP_001093326.2", "database": "RefSeq", "url": "" }, { "id": "NEMO_HUMAN", "database": "ZINC - Predictions - Purchasable", "url": "" }, { "id": "16252", "database": "Orphanet", "url": "" }, { "id": "3CL3", "database": "PDB", "url": "" }, { "id": "Q9Y6K9", "database": "ZINC target", "url": "" }, { "id": "5AAY", "database": "PDB", "url": "" }, { "id": "6MI3", "database": "PDB", "url": "" }, { "id": "5LDE", "database": "PDB", "url": "" }, { "id": "NP_001308325.1", "database": "RefSeq", "url": "" }, { "id": "NP_001138727.1", "database": "RefSeq", "url": "" }, { "id": "6YEK", "database": "PDB", "url": "" }, { "id": "ENST00000594239", "database": "Ensembl", "url": "" }, { "id": "ENSP00000483825", "database": "Ensembl", "url": "" }, { "id": "ENSP00000471166", "database": "Ensembl", "url": "" }, { "id": "ENSP00000478616", "database": "Ensembl", "url": "" }, { "id": "ENSP00000394934", "database": "Ensembl", "url": "" }, { "id": "ENSP00000390368", "database": "Ensembl", "url": "" }, { "id": "7T2U", "database": "PDB", "url": "" }, { "id": "7TV4", "database": "PDB", "url": "" }, { "id": "ENSP00000479662", "database": "Ensembl", "url": "" }, { "id": "ENST00000611071", "database": "Ensembl", "url": "" }, { "id": "ENSG00000269335", "database": "Ensembl", "url": "" }, { "id": "ENST00000422680", "database": "Ensembl", "url": "" }, { "id": "ENST00000440286", "database": "Ensembl", "url": "" }, { "id": "ENSG00000269335", "database": 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"https://www.uniprot.org/uniprot/O43318" } ] }, { "ec_number": "2.7.11.25", "activity": "", "evidence": [ { "id": "O43318", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O43318" } ] } ] }, { "uniprot_ac": "O43353", "gene_name": "RIPK2", "activity": [ { "ec_number": "2.7.10.2", "activity": "ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein].", "evidence": [ { "id": "O43353", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O43353" } ] }, { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "O43353", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O43353" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "O43353", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O43353" } ] } ] }, { "uniprot_ac": "O75604", "gene_name": "USP2", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "O75604", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O75604" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "O75604", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O75604" } ] } ] }, { "uniprot_ac": "O88351", "gene_name": "Ikbkb", "activity": [ { "ec_number": "2.7.11.10", "activity": "ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-seryl-[I-kappa-B protein].", "evidence": [ { "id": "O88351", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O88351" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "O88351", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O88351" } ] }, { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "O88351", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O88351" } ] } ] }, { "uniprot_ac": "O95786", "gene_name": "RIGI", "activity": [ { "ec_number": "3.6.4.13", "activity": "ATP + H2O = ADP + H(+) + phosphate.", "evidence": [ { "id": "O95786", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O95786" } ] }, { "ec_number": "3.6.4.13", "activity": "", "evidence": [ { "id": "O95786", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O95786" } ] } ] }, { "uniprot_ac": "P19525", "gene_name": "EIF2AK2", "activity": [ { "ec_number": "2.7.10.2", "activity": "ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein].", "evidence": [ { "id": "P19525", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P19525" } ] }, { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "P19525", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P19525" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "P19525", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P19525" } ] } ] }, { "uniprot_ac": "P21580", "gene_name": "TNFAIP3", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "P21580", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P21580" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "P21580", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P21580" } ] }, { "ec_number": "2.3.2.-", "activity": "", "evidence": [ { "id": "P21580", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P21580" } ] } ] }, { "uniprot_ac": "P31749", "gene_name": "AKT1", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "P31749", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P31749" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "P31749", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P31749" } ] } ] }, { "uniprot_ac": "P31751", "gene_name": "AKT2", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "P31751", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P31751" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "P31751", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P31751" } ] } ] }, { "uniprot_ac": "P41279", "gene_name": "MAP3K8", "activity": [ { "ec_number": "2.7.11.25", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "P41279", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P41279" } ] }, { "ec_number": "2.7.11.25", "activity": "", "evidence": [ { "id": "P41279", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P41279" } ] }, { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "P41279", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P41279" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "P41279", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P41279" } ] } ] }, { "uniprot_ac": "P51617", "gene_name": "IRAK1", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "P51617", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P51617" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "P51617", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P51617" } ] } ] }, { "uniprot_ac": "P54578", "gene_name": "USP14", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "P54578", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P54578" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "P54578", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P54578" } ] } ] }, { "uniprot_ac": "P61081", "gene_name": "UBE2M", "activity": [ { "ec_number": "2.3.2.34", "activity": "[E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine + [E2 NEDD8-conjugating enzyme]-L-cysteine = [E1 NEDD8-activating enzyme]-L-cysteine + [E2 NEDD8-conjugating enzyme]-S-[NEDD8-protein]-yl-L-cysteine.", "evidence": [ { "id": "P61081", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P61081" } ] }, { "ec_number": "2.3.2.34", "activity": "", "evidence": [ { "id": "P61081", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P61081" } ] } ] }, { "uniprot_ac": "P61088", "gene_name": "UBE2N", "activity": [ { "ec_number": "2.3.2.23", "activity": "S-ubiquitinyl-[E1 ubiquitin-activating enzyme]-L-cysteine + [E2 ubiquitin-conjugating enzyme]-L-cysteine = [E1 ubiquitin-activating enzyme]-L-cysteine + S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine.", "evidence": [ { "id": "P61088", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P61088" } ] }, { "ec_number": "2.3.2.23", "activity": "", "evidence": [ { "id": "P61088", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P61088" } ] } ] }, { "uniprot_ac": "P98170", "gene_name": "XIAP", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "P98170", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P98170" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "P98170", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/P98170" } ] } ] }, { "uniprot_ac": "Q04759", "gene_name": "PRKCQ", "activity": [ { "ec_number": "2.7.11.13", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q04759", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q04759" } ] }, { "ec_number": "2.7.11.13", "activity": "", "evidence": [ { "id": "Q04759", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q04759" } ] } ] }, { "uniprot_ac": "Q06187", "gene_name": "BTK", "activity": [ { "ec_number": "2.7.10.2", "activity": "ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein].", "evidence": [ { "id": "Q06187", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q06187" } ] }, { "ec_number": "2.7.10.2", "activity": "", "evidence": [ { "id": "Q06187", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q06187" } ] } ] }, { "uniprot_ac": "Q12933", "gene_name": "TRAF2", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q12933", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q12933" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q12933", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q12933" } ] } ] }, { "uniprot_ac": "Q13107", "gene_name": "USP4", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "Q13107", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13107" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "Q13107", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13107" } ] } ] }, { "uniprot_ac": "Q13233", "gene_name": "MAP3K1", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q13233", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13233" } ] }, { "ec_number": "2.7.11.25", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q13233", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13233" } ] }, { "ec_number": "2.7.11.25", "activity": "", "evidence": [ { "id": "Q13233", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13233" } ] } ] }, { "uniprot_ac": "Q13489", "gene_name": "BIRC3", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q13489", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13489" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q13489", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13489" } ] } ] }, { "uniprot_ac": "Q13490", "gene_name": "BIRC2", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q13490", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13490" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q13490", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13490" } ] } ] }, { "uniprot_ac": "Q13546", "gene_name": "RIPK1", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q13546", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13546" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "Q13546", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q13546" } ] } ] }, { "uniprot_ac": "Q14164", "gene_name": "IKBKE", "activity": [ { "ec_number": "2.7.11.10", "activity": "ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-seryl-[I-kappa-B protein].", "evidence": [ { "id": "Q14164", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q14164" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "Q14164", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q14164" } ] } ] }, { "uniprot_ac": "Q14258", "gene_name": "TRIM25", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q14258", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q14258" } ] }, { "ec_number": "6.3.2.n3", "activity": "ATP + [ISG15] + [protein]-lysine = AMP + diphosphate + [protein]-N-ISGyllysine.", "evidence": [ { "id": "Q14258", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q14258" } ] }, { "ec_number": "6.3.2.n3", "activity": "", "evidence": [ { "id": "Q14258", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q14258" } ] } ] }, { "uniprot_ac": "Q14790", "gene_name": "CASP8", "activity": [ { "ec_number": "3.4.22.61", "activity": "Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).", "evidence": [ { "id": "Q14790", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q14790" } ] }, { "ec_number": "3.4.22.61", "activity": "", "evidence": [ { "id": "Q14790", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q14790" } ] } ] }, { "uniprot_ac": "Q5VV17", "gene_name": "OTUD1", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "Q5VV17", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q5VV17" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "Q5VV17", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q5VV17" } ] } ] }, { "uniprot_ac": "Q60680", "gene_name": "Chuk", "activity": [ { "ec_number": "2.7.11.10", "activity": "ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-seryl-[I-kappa-B protein].", "evidence": [ { "id": "Q60680", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q60680" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "Q60680", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q60680" } ] } ] }, { "uniprot_ac": "Q6GQQ9", "gene_name": "OTUD7B", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "Q6GQQ9", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q6GQQ9" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "Q6GQQ9", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q6GQQ9" } ] } ] }, { "uniprot_ac": "Q8IUD6", "gene_name": "RNF135", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q8IUD6", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q8IUD6" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q8IUD6", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q8IUD6" } ] } ] }, { "uniprot_ac": "Q8TBC4", "gene_name": "UBA3", "activity": [ { "ec_number": "6.2.1.64", "activity": "ATP + [NEDD8 protein] + [E1 NEDD8-activating enzyme]-L-cysteine = AMP + diphosphate + [E1 NEDD8-activating enzyme]-S-[NEDD8 protein]-yl-L-cysteine.", "evidence": [ { "id": "Q8TBC4", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q8TBC4" } ] }, { "ec_number": "6.2.1.64", "activity": "", "evidence": [ { "id": "Q8TBC4", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q8TBC4" } ] } ] }, { "uniprot_ac": "Q92851", "gene_name": "CASP10", "activity": [ { "ec_number": "3.4.22.63", "activity": "Strict requirement for Asp at position P1 and has a preferred cleavage sequence of Leu-Gln-Thr-Asp-|-Gly.", "evidence": [ { "id": "Q92851", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q92851" } ] }, { "ec_number": "3.4.22.63", "activity": "", "evidence": [ { "id": "Q92851", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q92851" } ] } ] }, { "uniprot_ac": "Q96EP0", "gene_name": "RNF31", "activity": [ { "ec_number": "2.3.2.31", "activity": "[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.", "evidence": [ { "id": "Q96EP0", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q96EP0" } ] }, { "ec_number": "2.3.2.31", "activity": "", "evidence": [ { "id": "Q96EP0", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q96EP0" } ] } ] }, { "uniprot_ac": "Q96QP1", "gene_name": "ALPK1", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q96QP1", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q96QP1" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "Q96QP1", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q96QP1" } ] } ] }, { "uniprot_ac": "Q99558", "gene_name": "MAP3K14", "activity": [ { "ec_number": "2.7.11.25", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q99558", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q99558" } ] }, { "ec_number": "2.7.11.25", "activity": "", "evidence": [ { "id": "Q99558", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q99558" } ] } ] }, { "uniprot_ac": "Q9BYM8", "gene_name": "RBCK1", "activity": [ { "ec_number": "2.3.2.31", "activity": "[E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-N(6)-ubiquitinyl-L-lysine.", "evidence": [ { "id": "Q9BYM8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9BYM8" } ] }, { "ec_number": "2.3.2.31", "activity": "", "evidence": [ { "id": "Q9BYM8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9BYM8" } ] } ] }, { "uniprot_ac": "Q9BYX4", "gene_name": "IFIH1", "activity": [ { "ec_number": "3.6.4.13", "activity": "ATP + H2O = ADP + H(+) + phosphate.", "evidence": [ { "id": "Q9BYX4", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9BYX4" } ] }, { "ec_number": "3.6.4.13", "activity": "", "evidence": [ { "id": "Q9BYX4", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9BYX4" } ] } ] }, { "uniprot_ac": "Q9C037", "gene_name": "TRIM4", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q9C037", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9C037" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q9C037", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9C037" } ] } ] }, { "uniprot_ac": "Q9NQC7", "gene_name": "CYLD", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "Q9NQC7", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9NQC7" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "Q9NQC7", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9NQC7" } ] } ] }, { "uniprot_ac": "Q9QY78", "gene_name": "Ikbkb", "activity": [ { "ec_number": "2.7.11.10", "activity": "ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-seryl-[I-kappa-B protein].", "evidence": [ { "id": "Q9QY78", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9QY78" } ] }, { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q9QY78", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9QY78" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "Q9QY78", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9QY78" } ] } ] }, { "uniprot_ac": "Q9R0T8", "gene_name": "Ikbke", "activity": [ { "ec_number": "2.7.11.10", "activity": "ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-seryl-[I-kappa-B protein].", "evidence": [ { "id": "Q9R0T8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9R0T8" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "Q9R0T8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9R0T8" } ] } ] }, { "uniprot_ac": "Q9UDY8", "gene_name": "MALT1", "activity": [ { "ec_number": "3.4.22.-", "activity": "", "evidence": [ { "id": "Q9UDY8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9UDY8" } ] } ] }, { "uniprot_ac": "Q9UK80", "gene_name": "USP21", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "Q9UK80", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9UK80" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "Q9UK80", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9UK80" } ] } ] }, { "uniprot_ac": "Q9UMW8", "gene_name": "USP18", "activity": [ { "ec_number": "3.4.19.12", "activity": "Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).", "evidence": [ { "id": "Q9UMW8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9UMW8" } ] }, { "ec_number": "3.4.19.12", "activity": "", "evidence": [ { "id": "Q9UMW8", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9UMW8" } ] } ] }, { "uniprot_ac": "Q9VEZ5", "gene_name": "IKKbeta", "activity": [ { "ec_number": "2.7.11.10", "activity": "ATP + L-seryl-[I-kappa-B protein] = ADP + H(+) + O-phospho-L-seryl-[I-kappa-B protein].", "evidence": [ { "id": "Q9VEZ5", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9VEZ5" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "Q9VEZ5", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9VEZ5" } ] } ] }, { "uniprot_ac": "Q9Y243", "gene_name": "AKT3", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q9Y243", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9Y243" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "Q9Y243", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9Y243" } ] } ] }, { "uniprot_ac": "Q9Y4K3", "gene_name": "TRAF6", "activity": [ { "ec_number": "2.3.2.27", "activity": "S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.", "evidence": [ { "id": "Q9Y4K3", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9Y4K3" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q9Y4K3", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9Y4K3" } ] } ] }, { "uniprot_ac": "Q9Y572", "gene_name": "RIPK3", "activity": [ { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "Q9Y572", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9Y572" } ] }, { "ec_number": "2.7.11.1", "activity": "", "evidence": [ { "id": "Q9Y572", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q9Y572" } ] } ] } ], "biomarkers": [], 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