Phosphorylation and chromatin tethering prevent cGAS activation during mitosis

Science. 2021 Mar 19;371(6535):eabc5386. doi: 10.1126/science.abc5386.

Tuo Li ^# ¹ ² ³, Tuozhi Huang ^# ¹ ², Mingjian Du ¹ ², Xiang Chen ¹ ² ³, Fenghe Du ¹ ² ³, Junyao Ren ¹ ², Zhijian J Chen ⁴ ² ³

Affiliations

1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
2 Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
3 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
4 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. zhijian.chen@utsouthwestern.edu.
# Contributed equally.

PMID: 33542149 DOI: 10.1126/science.abc5386

Abstract

The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) detects microbial and self-DNA in the cytosol to activate immune and inflammatory programs. cGAS also associates with chromatin, especially after nuclear envelope breakdown when cells enter mitosis. How cGAS is regulated during cell cycle transition is not clear. Here, we found direct biochemical evidence that cGAS activity was selectively suppressed during mitosis in human cell lines and uncovered two parallel mechanisms underlying this suppression. First, cGAS was hyperphosphorylated at the N terminus by mitotic kinases, including Aurora Kinase B. The N terminus of cGAS was critical for sensing nuclear chromatin but not mitochondrial DNA. Chromatin sensing was blocked by hyperphosphorylation. Second, oligomerization of chromatin-bound cGAS, which is required for its activation, was prevented. Together, these mechanisms ensure that cGAS is inactive when associated with chromatin during mitosis, which may help to prevent autoimmune reaction.

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