Volume 11 Issue 8
Aug.  2020
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Mi Li, Hong-Bing Shu. Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response[J]. Protein&Cell, 2020, 11(8): 584-599. doi: 10.1007/s13238-020-00729-3
Citation: Mi Li, Hong-Bing Shu. Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response[J]. Protein&Cell, 2020, 11(8): 584-599. doi: 10.1007/s13238-020-00729-3

Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response

doi: 10.1007/s13238-020-00729-3

This work was supported by grants from the State Key R&D Program of China (2017YFA0505800, 2016YFA0502102), and the National Natural Science Foundation of China (Grant Nos. 31830024 and 31630045).

  • Received Date: 2020-03-29
  • The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosolic DNA derived from microbial pathogens or mis-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 serine 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.
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