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

Akhee Sabiha Jahan, Elise Biquand, Raquel Muñoz-Moreno, Agathe Le Quang, Chris Ka Pun Mok, Ho Him Wong, Qi Wen Teo, Sophie A. Valkenburg, Alex W.H. Chin, Leo Lit Man Poon, Artejan te Velthuis, Adolfo García-Sastre, Caroline Demeret, Sumana Sanyal

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 languageEnglish (US)
Pages (from-to)1570-1584.e6
JournalCell Reports
Volume30
Issue number5
DOIs
StatePublished - Feb 4 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • RIG-I signaling
  • RNA virus
  • deubiquitylases
  • influenza A
  • innate immune response
  • ubiquitylation
  • viral subversion strategies

Fingerprint

Dive into the research topics of 'OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1'. Together they form a unique fingerprint.

Cite this