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Phosphorylation and chromatin tethering prevent cGAS activation during mitosis
Tuo Li1,2,3, Tuozhi Huang1,2, Mingjian Du1,2
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Science (New York, N.Y.)
|February 5, 2021
Summary
Cyclic GMP-AMP synthase (cGAS) is suppressed during mitosis through hyperphosphorylation and blocked oligomerization. These mechanisms prevent cGAS activation when it associates with chromatin, potentially avoiding autoimmune reactions.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Cyclic GMP-AMP synthase (cGAS) is a key sensor of foreign and self-DNA, initiating immune and inflammatory responses.
- cGAS interacts with chromatin during mitosis following nuclear envelope breakdown, but its regulation during this cell cycle phase is unknown.
Purpose of the Study:
- To investigate the regulation of cGAS activity during mitosis.
- To identify the mechanisms suppressing cGAS function when associated with chromatin.
Main Methods:
- Biochemical assays in human cell lines.
- Analysis of cGAS phosphorylation and oligomerization during mitosis.
- Investigation of cGAS N-terminal domain function.
Main Results:
- cGAS activity is selectively suppressed during mitosis in human cells.
- Mitotic kinases, including Aurora kinase B, hyperphosphorylate the cGAS N terminus, blocking chromatin sensing.
- Hyperphosphorylation prevents the oligomerization of chromatin-bound cGAS, a prerequisite for its activation.
Conclusions:
- Two parallel mechanisms suppress cGAS activity during mitosis: N-terminal hyperphosphorylation and inhibited oligomerization.
- These regulatory processes ensure cGAS remains inactive when bound to chromatin, preventing potential autoimmune reactions.
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