cyclic-guanosine-monophosphate-adenosine-monophosphate and Herpes-Simplex

Topics: Animals; Antiviral Agents; Bystander Effect; Cell Line; Cells, Cultured; Embryo, Mammalian; Fibroblasts; HeLa Cells; Herpes Simplex; Herpesvirus 1, Human; Humans; Interferons; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Nucleotides, Cyclic; Nucleotidyltransferases; Voltage-Dependent Anion Channels

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.

Topics: Animals; Carboxypeptidases; Cytosol; DNA Virus Infections; DNA Viruses; DNA, Viral; Fluorescent Antibody Technique; Herpes Simplex; Immunoprecipitation; Interferon Regulatory Factor-3; Interferons; Mice; Mice, Knockout; Nucleotides, Cyclic; Nucleotidyltransferases; Peptide Synthases; Reverse Transcriptase Polymerase Chain Reaction; Simplexvirus; Vaccinia; Vaccinia virus

Cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA during virus infection and induces an antiviral state. cGAS signals by synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING). We show that cGAMP is incorporated into viral particles, including lentivirus and herpesvirus virions, when these are produced in cGAS-expressing cells. Virions transferred cGAMP to newly infected cells and triggered a STING-dependent antiviral program. These effects were independent of exosomes and viral nucleic acids. Our results reveal a way by which a signal for innate immunity is transferred between cells, potentially accelerating and broadening antiviral responses. Moreover, infection of dendritic cells with cGAMP-loaded lentiviruses enhanced their activation. Loading viral vectors with cGAMP therefore holds promise for vaccine development.

Topics: AIDS Vaccines; Dendritic Cells; Genes, Reporter; Genetic Vectors; HEK293 Cells; Herpes Simplex; Herpes Simplex Virus Vaccines; Herpesvirus 1, Human; HIV Infections; HIV-1; Humans; Immunity, Innate; Interferon-beta; Nucleotides, Cyclic; Promoter Regions, Genetic; Second Messenger Systems; Transcriptional Activation; Virion