title: A Viral Deamidase Targets the Helicase Domain of RIG-I to Block RNA-Induced Activation.
abstract: RIG-I detects double-stranded RNA (dsRNA) to trigger antiviral cytokine production. Protein deamidation is emerging as a post-translational modification that chiefly regulates protein function. We report here that UL37 of herpes simplex virus 1 (HSV-1) is a protein deamidase that targets RIG-I to block RNA-induced activation. Mass spectrometry analysis identified two asparagine residues in the helicase 2i domain of RIG-I that were deamidated upon UL37 expression or HSV-1 infection. Deamidation rendered RIG-I unable to sense viral dsRNA, thus blocking its ability to trigger antiviral immune responses and restrict viral replication. Purified full-length UL37 and its carboxyl-terminal fragment were sufficient to deamidate RIG-I in vitro. Uncoupling RIG-I deamidation from HSV-1 infection, by engineering deamidation-resistant RIG-I or introducing deamidase-deficient UL37 into the HSV-1 genome, restored RIG-I activation and antiviral immune signaling. Our work identifies a viral deamidase and extends the paradigm of deamidation-mediated suppression of innate immunity by microbial pathogens.
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Street, Los Angeles, CA 90033, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Street, Los Angeles, CA 90033, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Street, Los Angeles, CA 90033, USA.
authors.forename: Simin
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Street, Los Angeles, CA 90033, USA; Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Guobo
authors.initials: G
authors.lastname: Shen
authors.affiliation: Department of Chemistry, Dornsife College of Arts, Letters, and Sciences, University of Southern California, LJS 369, 840 Downey Way, Los Angeles, CA 90089, USA.
authors.forename: Caiqun
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Knipe
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Street, Los Angeles, CA 90033, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Division of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Biological Structure, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Chemistry, Dornsife College of Arts, Letters, and Sciences, University of Southern California, LJS 369, 840 Downey Way, Los Angeles, CA 90089, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410008, China.
authors.forename: Zanxian
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Street, Los Angeles, CA 90033, USA. Electronic address: pinghui.feng@usc.edu.
authors.forename: Pinghui
authors.initials: P
authors.lastname: Feng
mesh_terms: D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000998:Antiviral Agents / Q000276:immunology; D001216:Asparagine; D002460:Cell Line / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D000071457:DEAD Box Protein 58 / Q000187:drug effects / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism*; D004274:DNA, Recombinant; D004926:Escherichia coli / Q000235:genetics; D057809:HEK293 Cells / Q000821:virology; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D013058:Mass Spectrometry; D009154:Mutation; D011499:Protein Processing, Post-Translational; D012330:RNA, Double-Stranded; D012367:RNA, Viral / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins / Q000378:metabolism*; D015678:Viral Structural Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D004274:DNA, Recombinant; D012330:RNA, Double-Stranded; D012367:RNA, Viral; C084763:UL37 protein, Human herpesvirus 1; D014764:Viral Proteins; D015678:Viral Structural Proteins; D001216:Asparagine; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D000071457:DEAD Box Protein 58
keywords: ATPase/helicase; RIG-I; RNA-sensing; UL37; deamidation; herpesvirus; immune evasion