title: Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway.
abstract: The DNA sensing pathway triggers innate immune responses against DNA virus infection, and NF-κB signaling plays a critical role in establishing innate immunity. We report here that the herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP), which is a deubiquitinase (DUB), antagonizes NF-κB activation, depending on its DUB activity. In this study, ectopically expressed UL36USP blocked promoter activation of beta interferon (IFN-β) and NF-κB induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). UL36USP restricted NF-κB activation mediated by overexpression of STING, TANK-binding kinase 1, IκB kinase α (IKKα), and IKKβ, but not p65. UL36USP was also shown to inhibit IFN-stimulatory DNA-induced IFN-β and NF-κB activation under conditions of HSV-1 infection. Furthermore, UL36USP was demonstrated to deubiquitinate IκBα and restrict its degradation and, finally, abrogate NF-κB activation. More importantly, the recombinant HSV-1 lacking UL36USP DUB activity, denoted as C40A mutant HSV-1, failed to cleave polyubiquitin chains on IκBα. For the first time, UL36USP was shown to dampen NF-κB activation in the DNA sensing signal pathway to evade host antiviral innate immunity.IMPORTANCEIt has been reported that double-stranded-DNA-mediated NF-κB activation is critical for host antiviral responses. Viruses have established various strategies to evade the innate immune system. The N terminus of the HSV-1 UL36 gene-encoded protein contains the DUB domain and is conserved across all herpesviruses. This study demonstrates that UL36USP abrogates NF-κB activation by cleaving polyubiquitin chains from IκBα and therefore restricts proteasome-dependent degradation of IκBα and that DUB activity is indispensable for this process. This study expands our understanding of the mechanisms utilized by HSV-1 to evade the host antiviral innate immune defense induced by NF-κB signaling.
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China.
authors.forename: Ruijie
authors.initials: R
authors.lastname: Ye
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China.
authors.forename: Chenhe
authors.initials: C
authors.lastname: Su
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China zheng.alan@hotmail.com.|Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction; D054875:Ubiquitination; D014709:Vero Cells; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D016328:NF-kappa B; C078035:UL36 protein, Human herpesvirus 1; D014764:Viral Proteins; D016899:Interferon-beta
keywords: DNA sensor; HSV-1; IκBα; NF-κB; UL36