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.
Original language | English (US) |
---|---|
Pages (from-to) | 1570-1584.e6 |
Journal | Cell Reports |
Volume | 30 |
Issue number | 5 |
DOIs | |
State | Published - Feb 4 2020 |
Externally published | Yes |
All Science Journal Classification (ASJC) codes
- General Biochemistry, Genetics and Molecular Biology
Keywords
- RIG-I signaling
- RNA virus
- deubiquitylases
- influenza A
- innate immune response
- ubiquitylation
- viral subversion strategies