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Review
. 2021 Dec 30;13(10):721-727.
doi: 10.1093/jmcb/mjab061.

Mitotic inactivation of the cGAS‒MITA/STING pathways

Li Zhong  1 , Hong-Bing Shu  1
Affiliations
Review

Mitotic inactivation of the cGAS‒MITA/STING pathways

Li Zhong et al. J Mol Cell Biol. .

Abstract

The cyclic guanosine monophosphate‒adenosine monophosphate synthase (cGAS)‒mediator of interferon response factor 3 activation/stimulator of interferon genes (MITA/STING) axis has emerged as a major pathway, which senses microbial or mislocated cellular DNA in the cytosol to trigger innate immune responses. cGAS senses cytosolic DNA without a preference of self- or nonself-DNA. How the cGAS‒MITA/STING axis is inactivated upon nuclear envelope breakdown (NEBD) at mitotic entry in vertebrate cells to avoid self-DNA sensing remains unclear until very recently. In this review, we summarize the recent advances on how cGAS responds to chromosomes upon NEBD and the mechanisms involved in the inactivation of the cGAS‒MITA/STING pathways in mitosis.

Keywords: DNA; MITA; STING; cGAS; innate immune response; mitosis.

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Figures

Figure 1
Figure 1
Reorganization and inactivation of cGAS‒MITA/STING pathways during mitosis. (A) In interphase, cGAS senses cytosolic dsDNA with the DNA binding sites A, B, and C, resulting in the formation of dsDNA‒cGAS liquid droplets in which cGAS synthesizes cGAMP with ATP and GTP. cGAMP binds to the ER-located MITA/STING, which then translocates to the Golgi apparatus. In this process, MITA/STING recruits and activates TBK1, which then transphosphorylates the adjacent MITA/STING. Phosphorylated MITA then recruits IRF3 for its phosphorylation by TBK1, leading to activation of IRF3 and eventual induction of antiviral genes. (B) In mitosis, (1) cGAS is translocated into the nucleus upon NEBD and phosphorylated by mitotic kinases (e.g. CDK1 and AURKB) at distinct sites, leading to inhibition of its activity; (2) at chromosomes, cGAS binds to the nucleosome core particles with sites B and C, which impairs its interaction with DNA and disrupts its dimerization; (3) mitotic Golgi vesiculation suppresses MITA/STING and IRF3 activation. TBK1 is phosphorylated in mitosis but unable to phosphorylate IRF3, probably due to loss of MITA/STING-mediated regulation.
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