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      Herpes Simplex Virus 1 Ubiquitin-Specific Protease UL36 Abrogates NF-κB Activation in DNA Sensing Signal Pathway

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          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.

          IMPORTANCE It 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.

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          Author and article information

          Contributors
          Role: Editor
          Journal
          J Virol
          J. Virol
          jvi
          jvi
          JVI
          Journal of Virology
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0022-538X
          1098-5514
          28 December 2016
          14 February 2017
          1 March 2017
          : 91
          : 5
          : e02417-16
          Affiliations
          [a ]Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China
          [b ]Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
          University of California, Irvine
          Author notes
          Address correspondence to Chunfu Zheng, zheng.alan@ 123456hotmail.com .

          R.Y. and C.S. contributed equally to this article.

          Citation Ye R, Su C, Xu H, Zheng C. 2017. Herpes simplex virus 1 ubiquitin-specific protease UL36 abrogates NF-κB activation in DNA sensing signal pathway. J Virol 91:e02417-16. https://doi.org/10.1128/JVI.02417-16.

          Article
          PMC5309955 PMC5309955 5309955 02417-16
          10.1128/JVI.02417-16
          5309955
          28031360
          3b499a38-434f-4de8-92b3-ba5f0006f4d1
          Copyright © 2017 American Society for Microbiology.

          All Rights Reserved.

          History
          : 15 December 2016
          : 19 December 2016
          Page count
          Figures: 4, Tables: 0, Equations: 0, References: 59, Pages: 10, Words: 6146
          Funding
          Funded by: Innovative Research Team in Soochow University
          Award ID: PCSIRT IRT1075
          Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions
          Award ID: YX13400214
          Funded by: National Natural Science Foundation of China (NSFC) https://doi.org/10.13039/501100001809
          Award ID: 81371795
          Award ID: 81571974
          Categories
          Virus-Cell Interactions
          Custom metadata
          March 2017

          IκBα,HSV-1,DNA sensor,UL36,NF-κB
          IκBα, HSV-1, DNA sensor, UL36, NF-κB

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