title: Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3.
abstract: Interferon (IFN)-mediated innate immune defense is a potent antiviral mechanism. Viruses evade innate immunity and limit secretion of beta interferon (IFN-β) to replicate and survive in the host. The largest tegument protein of herpes simplex virus 1 (HSV-1), UL36, contains a novel deubiquitinase (DUB) motif embedded in its N terminus, denoted UL36 ubiquitin-specific protease (UL36USP). In the present study, we demonstrate that HSV-1 UL36USP inhibits Sendai virus (SeV)-induced interferon regulatory factor 3 (IRF3) dimerization, promoter activation, and transcription of IFN-β. The DUB activity of UL36USP is essential to block IFN-β production. UL36USP also inhibited IFN-β promoter activity induced by overexpression of the N terminus of RIG-I (RIG-IN) and MAVS, but not TBK-1, IκB kinase ε (IKKε), and IRF3/5D. UL36USP was subsequently shown to deubiquitinate TRAF3 and prevent the recruitment of the downstream adaptor TBK1. The recombinant HSV-1 lacking UL36USP DUB activity was generated. Cells infected with the mutant virus produced more IFN-β than wild-type (WT) HSV-1-infected cells. These findings demonstrate HSV-1 UL36USP removes polyubiquitin chains on TRAF3 and counteracts the IFN-β pathway.
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China;
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Kezhen
authors.initials: K
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Chunfu
authors.initials: C
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002460:Cell Line; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D029082:Sendai virus / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D048008:TNF Receptor-Associated Factor 3; C078035:UL36 protein, Human herpesvirus 1; D025801:Ubiquitin; D014764:Viral Proteins; D016899:Interferon-beta; D064570:Ubiquitin-Specific Proteases