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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carboxypeptidases / genetics*
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Cytosol
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DNA Virus Infections / metabolism*
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DNA Viruses / genetics
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DNA, Viral / immunology*
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Fluorescent Antibody Technique
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Herpes Simplex / metabolism
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Immunoprecipitation
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Interferon Regulatory Factor-3 / immunology
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Interferons / immunology
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Mice
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Mice, Knockout
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Nucleotides, Cyclic / biosynthesis
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Nucleotidyltransferases / immunology
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Nucleotidyltransferases / metabolism*
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Peptide Synthases / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Simplexvirus / genetics
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Vaccinia / metabolism
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Vaccinia virus / genetics
Substances
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DNA, Viral
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Interferon Regulatory Factor-3
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Irf3 protein, mouse
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Nucleotides, Cyclic
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cyclic guanosine monophosphate-adenosine monophosphate
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Interferons
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Nucleotidyltransferases
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cGAS protein, mouse
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CCP5 protein, mouse
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CCP6 protein, mouse
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Carboxypeptidases
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Peptide Synthases
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TTLL6 protein, mouse