Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis

Li Zhong,Li-Jun Bian,Qiang Chen,Ming-Ming Hu,Hong-Bing Shu,Ying Liu

doi:10.1038/s41421-020-0162-2

Li Zhong, Li-Jun Bian + Show 4 more

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https://doi.org/10.1038/s41421-020-0162-2

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Abstract

The cyclic GMP-AMP synthase (cGAS) is a widely used DNA sensor, which detects cytosolic DNA species without a preference of self or non-self microbial DNA in interphase to initiate innate immune response. How cGAS is regulated to avoid self-DNA sensing upon nuclear envelope breakdown (NEBD) during mitosis remains enigmatic. Here we show that cGAS is mostly localized in the cytoplasm in interphase and rapidly translocated to chromosomes upon NEBD in mitosis. The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry. The type 1 phosphatase PP1 dephosphorylates cGAS upon mitotic exit to enable its DNA sensing ability. Our findings reveal a mechanism on how the DNA sensor cGAS is post-translationally regulated by cell cycle-dependent enzymes to ensure its proper activation for host defense of cytosolic DNA in interphase and inert to self-DNA in mitosis.

Highlights

Introduction MicrobialDNA represents a key pathogen-associated molecular pattern (PAMP) that is sensed by host cells during infection[1,2]
The fact that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) translocate to chromosomes upon nuclear envelope breakdown (NEBD) poses an important question on why cGAS is inert to sense self-DNA in mitosis
We found that cGAS purified from mitotic cells lost its ability to synthesize cyclic GMP-AMP (cGAMP), suggesting that cGAS is not capable of sensing self-DNA in mitotic cells

Summary

Introduction

Introduction MicrobialDNA represents a key pathogen-associated molecular pattern (PAMP) that is sensed by host cells during infection[1,2]. Self-DNA sensing can be prevented by compartmentalization in which self-DNA is sequestered from the cytosol by nuclear envelope or other organelle membranes[1,3]. The nuclear envelope dissembles at mitotic entry in vertebrate cells[4], and the expose of self-DNA to cytosolic sensors raises a question on how mitotic cells restrain innate immunity to avert immune damage. The cyclic GMP-AMP synthase cGAS is a well-known cytosolic DNA sensor that detects the presence of invaded microbial DNA or self-DNA released into cytoplasm under genomic or mitochondrial stress and senescence[5,6,7,8,9,10]. Upon binding to DNA, cGAS utilizes GTP and ATP as substrates to synthesize the second messenger 2ʹ,3ʹ-cyclic GMP-AMP (cGAMP), which in turn binds to the ER-located adaptor

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