title: Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity.
abstract: Cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA during viral infection and catalyzes synthesis of the dinucleotide cGAMP, which activates the adaptor STING to initiate antiviral responses. Here we found that deficiency in the carboxypeptidase CCP5 or CCP6 led to susceptibility to DNA viruses. CCP5 and CCP6 were required for activation of the transcription factor IRF3 and interferons. Polyglutamylation of cGAS by the enzyme TTLL6 impeded its DNA-binding ability, whereas TTLL4-mediated monoglutamylation of cGAS blocked its synthase activity. Conversely, CCP6 removed the polyglutamylation of cGAS, whereas CCP5 hydrolyzed the monoglutamylation of cGAS, which together led to the activation of cGAS. Therefore, glutamylation and deglutamylation of cGAS tightly modulate immune responses to infection with DNA viruses.
authors.affiliation: Key Laboratory of Infection and Immunity of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Pengyan
authors.initials: P
authors.lastname: Xia
authors.affiliation: Key Laboratory of Infection and Immunity of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Buqing
authors.initials: B
authors.lastname: Ye
authors.affiliation: Key Laboratory of Infection and Immunity of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Infection and Immunity of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.affiliation: Key Laboratory of Infection and Immunity of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|Beijing Key Laboratory of Noncoding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Key Laboratory of Infection and Immunity of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D000818:Animals; D002268:Carboxypeptidases / Q000235:genetics*; D003600:Cytosol; D004266:DNA Virus Infections / Q000378:metabolism*; D004267:DNA Viruses / Q000235:genetics; D004279:DNA, Viral / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006561:Herpes Simplex / Q000378:metabolism; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D007372:Interferons / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009712:Nucleotides, Cyclic / Q000096:biosynthesis; D009713:Nucleotidyltransferases / Q000276:immunology / Q000378:metabolism*; D010453:Peptide Synthases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics; D014615:Vaccinia / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D002268:Carboxypeptidases; D004279:DNA, Viral; D050838:Interferon Regulatory Factor-3; D007372:Interferons; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D010453:Peptide Synthases; C494233:Irf3 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C000609738:CCP5 protein, mouse; C000596944:CCP6 protein, mouse; C585750:TTLL6 protein, mouse
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