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The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosollc DNA derived from microbial pathogens or mls-located cellular DNA.Upon DNA binding,cGAS utilizes GTP and ATP as substrates to synthesize cGAMP,leading to MITA-mediated innate immune response.In this study,we identified the phosphatase PPP6C as a negative regulator of cGASmediated innate immune response.PPP6C is constitutively associated with cGAS in un-stimulated cells.DNA virus infection causes rapid disassociation of PPP6C from cGAS,resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket.Mutation of this eerine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection.In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity.PPP6Cdeficiency promotes innate immune response to DNA virus in various cells.Our findings suggest that PPP6Cmediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response,which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.