TY - JOUR
T1 - Phosphorylation and chromatin tethering prevent cGAS activation during mitosis
AU - Li, Tuo
AU - Huang, Tuozhi
AU - Du, Mingjian
AU - Chen, Xiang
AU - Du, Fenghe
AU - Ren, Junyao
AU - Chen, Zhijian J.
N1 - Funding Information:
Work in the Chen laboratory is supported by grants from the National Cancer Institute (U54CA244719), Welch Foundation (I-1389), and Cancer Prevention and Research Institute of Texas (RP180725). T.L. was supported by a postdoctoral fellowship from the Cancer Research Institute. Z.J.C. is an investigator of the Howard Hughes Medical Institute.
Funding Information:
We thank B. Ramirez for assisting in the maintenance of our mass spectrometry facility. We thank M. Li and J. Cabrera for editing the manuscript and figures, respectively. Funding: Work in the Chen laboratory is supported by grants from the National Cancer Institute
Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/3/19
Y1 - 2021/3/19
N2 - 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.
AB - 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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U2 - 10.1126/science.abc5386
DO - 10.1126/science.abc5386
M3 - Article
C2 - 33542149
AN - SCOPUS:85100985604
SN - 0036-8075
VL - 371
JO - Science
JF - Science
IS - 6535
M1 - eabc5386
ER -