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

doi:10.1007/s13238-020-00729-3

Protein Cell

2020, Vol. 11

Issue (8) : 584-599 https://doi.org/10.1007/s13238-020-00729-3

RESEARCH ARTICLE

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

Mi Li, Hong-Bing Shu(

)

Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan 430071, China

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Abstract

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.

Keywords DNA virus PPP6C cGAS innate immune response phosphorylation substrate binding

Corresponding Author(s): Hong-Bing Shu

Issue Date: 26 August 2020

Cite this article:

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.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-020-00729-3
https://academic.hep.com.cn/pac/EN/Y2020/V11/I8/584

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