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-5357845", "name": "K63polyUb-RIPK1 is deubiquitinated", "equation": "", "summary": "K63-deubiquitination of RIP1 abolishes its ability to activate NF-kappa-B upon TNF-alpha stimulation and leads to the formation of the cytosolic caspase-8 containing complex II and subsequent apoptosis.", "cellular_location": "cytosol, plasma membrane", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "Q5VV17-1", "Q12933-1", "Q13107-1", "O75604-1", "P98170-1", "Q13546-1", "P21580-1", "Q13490-1", "Q13489-1", "Q6GQQ9-1", "Q9NQC7-1", "Q9UK80-1" ], "evidence": [ { "id": "R-HSA-5357845", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5357845" } ] }, { "id": "R-HSA-5357860", "name": "TNF:TNFR1:TRADD:TRAF2:K63polyUb-RIPK1:BIRC2/3:LUBAC recruits TAK1 complex", "equation": "", "summary": "Polyubiquitinated RIPK1 binds to TAB2 resulting in the recruitment of the TAB2:TAK1 complex. The K63-linked ubiqitination on Lys377 of RIPK1 was shown to mediate the association of RIPK1 with the TAB2:TAK1 complex (Li H et al. 2006)", "cellular_location": "cytosol, plasma membrane", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "Q96EP0-1", "Q9BYM8-1", "Q5VV17-1", "O43318-1", "Q12933-1", "Q13107-1", "O75604-1", "P98170-1", "Q13546-1", "P21580-1", "Q13490-1", "Q13489-1", "Q6GQQ9-1", "Q9NQC7-1", "Q9UK80-1" ], "evidence": [ { "id": "R-HSA-5357860", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5357860" } ] }, { "id": "R-HSA-5689972", "name": "USP2 deubiquitinates MDM2,MDM4", "equation": "", "summary": "The ubiquitin protease USP2 deubiquitinates MDM2 and MDM4 but not TP53 (Stevenson et al. 2007, Allende-Vega et al. 2010).", "cellular_location": "nucleoplasm", "input_participant_list": [], "output_participant_list": [ "R-HSA-5689946" ], "enzyme_list": [ "O75604-1", "Q00987-1" ], "evidence": [ { "id": "R-HSA-5689972", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-5689972" } ] }, { "id": "R-HSA-6805022", "name": "USP2 binds the heterodimer of MDM2 and MDM4", "equation": "", "summary": "The ubiquitin protease USP2 forms a tripartite complex with MDM2 and MDM4 (MDMX) by binding to the ubiquitinated heterodimer of MDM2 and MDM4 (Allende-Vega et al. 2010).", "cellular_location": "nucleoplasm", "input_participant_list": [], "output_participant_list": [], "enzyme_list": [ "O75604-1", "Q00987-1" ], "evidence": [ { "id": "R-HSA-6805022", "database": "Reactome", "url": "https://www.reactome.org/PathwayBrowser/#R-HSA-6805022" } ] } ], "reaction_participants": [ { "participant_id": "R-HSA-5689946", "participant_name": "USP2 [nucleoplasm]", "crossref": [ { "id": "2IBI", "database": "PDB", "url": "" }, { "id": "6DGF", "database": "PDB", "url": "" }, { "id": "5XVE", "database": "PDB", "url": "" }, { "id": "2430", "database": "Guide to Pharmacology - Targets", "url": "" }, { "id": "HMDBP11576", "database": "HMDB Protein", "url": "" }, { "id": "NP_004196.4", "database": "RefSeq", "url": "" }, { "id": "O75604", "database": "PRO", "url": "" }, { "id": "ENSP00000260187", "database": "Ensembl", "url": "" }, { "id": "ENSP00000436952", "database": "Ensembl", "url": "" }, { "id": "3NHE", "database": "PDB", "url": "" }, { "id": "XP_005271778.1", "database": "RefSeq", "url": "" }, { "id": "3V6E", "database": "PDB", "url": "" }, { "id": "O75604", "database": "GeneCards", "url": "" }, { "id": "ENSP00000407842", "database": "Ensembl", "url": "" }, { "id": "O75604", "database": "UniProt", "url": "" }, { "id": "5XU8", "database": "PDB", "url": "" }, { "id": "2HD5", "database": "PDB", "url": "" }, { "id": "O75604", "database": "ZINC target", "url": "" }, { "id": "NP_741994.1", "database": "RefSeq", "url": "" }, { "id": "3V6C", "database": "PDB", "url": "" }, { "id": "ENSG00000036672-USP2", "database": "HPA", "url": "" }, { "id": "ENST00000260187", "database": "Ensembl", "url": "" }, { "id": "ENST00000525735", "database": "Ensembl", "url": "" }, { "id": "NP_001230688.1", "database": "RefSeq", "url": "" }, { "id": "3.4.19.12", "database": "IntEnz", "url": "" }, { "id": "ENSG00000036672", "database": "OpenTargets", "url": "" }, { "id": "O75604", "database": "Pharos - Targets", "url": "" }, { "id": "ENST00000455332", "database": "Ensembl", "url": "" }, { "id": "ENSG00000036672", "database": "Ensembl", "url": "" }, { "id": "XP_005271779.1", "database": "RefSeq", "url": "" } ] } ], "reaction_enzymes": [ { "uniprot_ac": "O14920", "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": "O14920", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O14920" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "O14920", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O14920" } ] }, { "ec_number": "2.7.11.1", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "O14920", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O14920" } ] } ] }, { "uniprot_ac": "O15111", "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": "O15111", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O15111" } ] }, { "ec_number": "2.7.11.10", "activity": "", "evidence": [ { "id": "O15111", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/O15111" } ] } ] }, { "uniprot_ac": "O43318", "gene_name": "MAP3K7", "activity": [ { "ec_number": "2.7.11.25", "activity": "ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein].", "evidence": [ { "id": "O43318", "database": "UniProtKB", "url": "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": "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": "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": "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": "Q00987", "gene_name": "MDM2", "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": "Q00987", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q00987" } ] }, { "ec_number": "2.3.2.27", "activity": "", "evidence": [ { "id": "Q00987", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q00987" } ] } ] }, { "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": "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": "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": "Q6GQQ9", "gene_name": "OTUD7B", 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"id": "Q96EP0", "database": "UniProtKB", "url": "https://www.uniprot.org/uniprot/Q96EP0" } ] } ] }, { "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": "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": 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"o_linked_glycans", "count": 0 }, { "field": "o_linked_glycan_sites", "count": 0 } ], "sort_fields": [] }, { "table_id": "glycosylation_reported_with_glycan", "table_stats": [ { "field": "total", "count": 1 }, { "field": "total_sites", "count": 1 }, { "field": "n_linked_glycans", "count": 0 }, { "field": "n_linked_glycan_sites", "count": 0 }, { "field": "o_linked_glycans", "count": 1 }, { "field": "o_linked_glycan_sites", "count": 1 } ], "sort_fields": [ "glytoucan_ac", "type", "subtype", "site_category", "site_seq", "relation", "comment" ] }, { "table_id": "glycosylation_predicted", "table_stats": [ { "field": "total", "count": 0 }, { "field": "total_sites", "count": 0 }, { "field": "n_linked_glycans", "count": 0 }, { "field": "n_linked_glycan_sites", "count": 0 }, { "field": "o_linked_glycans", "count": 0 }, { "field": "o_linked_glycan_sites", "count": 0 } ], "sort_fields": [] }, { "table_id": "glycosylation_automatic_literature_mining", "table_stats": [ { "field": "total", "count": 0 }, { "field": "total_sites", "count": 0 }, { "field": "n_linked_glycans", "count": 0 }, { "field": "n_linked_glycan_sites", "count": 0 }, { "field": "o_linked_glycans", "count": 0 }, { "field": "o_linked_glycan_sites", "count": 0 } ], "sort_fields": [] }, { "table_id": "phosphorylation", "table_stats": [ { "field": "total", "count": 0 }, { "field": "total_sites", "count": 0 } ], "sort_fields": [] }, { "table_id": "snv", "table_stats": [ { "field": "total", "count": 1 }, { "field": "total_sites", "count": 1 } ], "sort_fields": [ "start_pos", "end_pos", "subjects_tested", "subjects_positive", "frequency", "sequence_org", "sequence_mut", "comment", "chr_id", "chr_pos", "ref_nt", "alt_nt", "minor_allelic_frequency", "site_lbl" ] }, { "table_id": "snv_disease", "table_stats": [ { "field": "total", "count": 1 }, { "field": "total_sites", "count": 1 } ], "sort_fields": [ "start_pos", "end_pos", "subjects_tested", "subjects_positive", "frequency", "sequence_org", "sequence_mut", "comment", 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