Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Science. 2021 Mar 19;371(6535). doi: 10.1126/science.abc5386. Epub 2021 Feb 4.
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.
环鸟苷酸-腺苷酸合酶 (cGAS) 在细胞质中检测微生物和自身 DNA，以激活免疫和炎症程序。cGAS 还与染色质相关联，特别是在核膜破裂后细胞进入有丝分裂时。cGAS 在细胞周期转换期间如何受到调节尚不清楚。在这里，我们发现了直接的生化证据，表明 cGAS 活性在人细胞系的有丝分裂过程中被选择性抑制，并揭示了这种抑制的两种并行机制。首先，有丝分裂激酶（包括 Aurora 激酶 B）使 cGAS 的 N 端发生过度磷酸化。cGAS 的 N 端对于感知核染色质但不是线粒体 DNA 至关重要。磷酸化过度会阻止染色质感应。其次，染色质结合的 cGAS 寡聚化被阻止，这是其激活所必需的。总之，这些机制确保了 cGAS 在有丝分裂过程中与染色质结合时处于非活性状态，这可能有助于防止自身免疫反应。
