@article{199bee9f982241e085134dec020a08c4,
title = "OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1",
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.",
keywords = "RIG-I signaling, RNA virus, deubiquitylases, influenza A, innate immune response, ubiquitylation, viral subversion strategies",
author = "Jahan, {Akhee Sabiha} and Elise Biquand and Raquel Mu{\~n}oz-Moreno and {Le Quang}, Agathe and Mok, {Chris Ka Pun} and Wong, {Ho Him} and Teo, {Qi Wen} and Valkenburg, {Sophie A.} and Chin, {Alex W.H.} and {Man Poon}, {Leo Lit} and {te Velthuis}, Artejan and Adolfo Garc{\'i}a-Sastre and Caroline Demeret and Sumana Sanyal",
note = "Funding Information: This work was funded by Research Grants Council (GRF) grants 17113915 and 17112617 and partially supported by Health and Medical Research Funds (16150592), a theme-based research grant from the Research Grants Council (project T11-705/14N), and PTR (546) from Institut Pasteur. S.S. is supported by the Croucher Foundation. The authors thank Michael Weekes and Benedikt Kessler for suggestions regarding mass spectrometry analyses. S.S. was responsible for the overall design of the study. A.S.J. E.B. R.M.-M. C.K.-P.M. H.H.W. A.L.Q. and Q.W.T. performed the experiments. A.W.H.C. R.M.-M. L.L.M.P. C.D. and A.G.-S. were involved in generation and characterization of constructs, recombinant viruses, and cell lines critical to the study. The authors declare no competing interests. Funding Information: This work was funded by Research Grants Council (GRF) grants 17113915 and 17112617 and partially supported by Health and Medical Research Funds ( 16150592 ), a theme-based research grant from the Research Grants Council (project T11-705/14N ), and PTR (546) from Institut Pasteur . S.S. is supported by the Croucher Foundation . The authors thank Michael Weekes and Benedikt Kessler for suggestions regarding mass spectrometry analyses. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = feb,
day = "4",
doi = "10.1016/j.celrep.2020.01.015",
language = "English (US)",
volume = "30",
pages = "1570--1584.e6",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}