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OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Jahan, Akhee Sabiha 
Biquand, Elise 
Muñoz-Moreno, Raquel 
Le Quang, Agathe 
Mok, Chris Ka-Pun 

Abstract

Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [35S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses.

Description

Keywords

RIG-I signaling, RNA virus, deubiquitylases, influenza A, innate immune response, ubiquitylation, viral subversion strategies, A549 Cells, Animals, Cysteine Endopeptidases, Cytosol, DEAD Box Protein 58, Deubiquitinating Enzymes, Dogs, Gene Deletion, HEK293 Cells, Humans, Influenza, Human, Interferon Regulatory Factor-3, Interferon Type I, Madin Darby Canine Kidney Cells, Male, Mitochondrial Membranes, NF-kappa B, Proteasome Endopeptidase Complex, Protein Multimerization, Proteolysis, Receptors, Immunologic, Signal Transduction, Viral Nonstructural Proteins

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

30

Publisher

Elsevier BV