Phosphorylation and chromatin tethering prevent cGAS activation during mitosis

Science. 2021 Mar 19;371(6535):eabc5386. doi: 10.1126/science.abc5386. Epub 2021 Feb 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase B / metabolism
  • Cell Cycle
  • Cell Line
  • Chromatin / metabolism*
  • DNA / metabolism
  • DNA, Mitochondrial / metabolism
  • Enzyme Activation
  • Humans
  • Mitosis*
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / chemistry
  • Nucleotidyltransferases / metabolism*
  • Phosphorylation
  • Protein Multimerization

Substances

  • Chromatin
  • DNA, Mitochondrial
  • Nucleotides, Cyclic
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA
  • AURKB protein, human
  • Aurora Kinase B
  • Nucleotidyltransferases
  • cGAS protein, human