Journal
CELL REPORTS
Volume 30, Issue 5, Pages 1570-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.01.015
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Funding
- Research Grants Council (GRF) [17113915, 17112617]
- Health and Medical Research Funds [16150592]
- Research Grants Council [T11-705/14N]
- Institut Pasteur [PTR (546)]
- Croucher Foundation
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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 mitochondria, 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 [S-35]IRF3, purified RIG-I, mitochondria! 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.
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