
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.05.611502
preprint
1
Article
Paramyxovirus matrix proteins modulate host cell translation via exon-junction complex interactions in the cytoplasm
Hung Chuan-Tien http://orcid.org/0000-0001-6899-1312

Haas Griffin D
Watkinson Ruth E http://orcid.org/0000-0001-6218-6785

Chiu Hsin-Ping http://orcid.org/0000-0002-5010-7338

Kowdle Shreyas http://orcid.org/0000-0002-7786-3547

Stevens Christian S http://orcid.org/0000-0003-2472-6984

Park Arnold http://orcid.org/0000-0001-8916-2230

Wohlschlegel James A http://orcid.org/0000-0003-3399-901X

Thibault Patricia A http://orcid.org/0000-0002-7313-0848

Lee Benhur http://orcid.org/0000-0003-0760-1709

07 9 2024
2024.09.05.611502https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.05.611502
nihpp-2024.09.05.611502.pdf
ABSTRACT

Viruses have evolved myriad strategies to exploit the translation machinery of host cells to potentiate their replication. However, how paramyxovirus (PMVs) modulate cellular translation for their own benefit has not been systematically examined. Utilizing puromycylation labeling, overexpression of individual viral genes, and infection with wild-type virus versus its gene-deleted counterpart, we found that PMVs significantly inhibit host cells’ nascent peptide synthesis during infection, with the viral matrix being the primary contributor to this effect. Using the rNiV-NPL replicon system, we discovered that the viral matrix enhances viral protein translation without affecting viral mRNA transcription and suppresses host protein expression at the translational level. Polysome profile analysis revealed that the HPIV3 matrix promotes the association of viral mRNAs with ribosomes, thereby enhancing their translation efficiency during infection. Intriguingly, our NiV-Matrix interactome identified the core exon-junction complex (cEJC), critical for mRNA biogenesis, as a significant component that interacts with the paramyxoviral matrix predominantly in the cytoplasm. siRNA knockdown of eIF4AIII simulated the restriction of cellular functions by the viral matrix, leading to enhanced viral gene translation and a reduction in host protein synthesis. Moreover, siRNA depletion of cEJC resulted in a 2-3 log enhancement in infectious virus titer for various PMVs but not SARS-CoV-2, enterovirus D68, or influenza virus. Our findings characterize a host translational interference mechanism mediated by viral matrix and host cEJC interactions. We propose that the PMV matrix redirects ribosomes to translate viral mRNAs at the expense of host cell transcripts, enhancing viral replication, and thereby enhancing viral replication. These insights provide a deeper understanding of the molecular interactions between paramyxoviruses and host cells, highlighting potential targets for antiviral strategies.
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pmc
