2021年2月4日，美国德克萨斯大学西南医学中心陈志坚小组在《科学》杂志发表论文，他们发现磷酸化和染色质束缚抑制有丝分裂过程中环GMP-AMP合酶（cGAS）的活化。

研究人员发现了直接的生化证据来证明在有丝分裂过程中cGAS活性被选择性抑制，并揭示了这种抑制的两个平行机制。首先，cGAS的N端被包括Aurora激酶B在内的有丝分裂激酶磷酸化。cGAS的N端对于感知核染色质而非线粒体DNA至关重要。染色质感知被过度磷酸化所阻断。其次，cGAS激活所需的与染色质结合寡聚化被抑制。

这些机制共同确保在有丝分裂期过程中，与染色质结合时cGAS的失活，这可能有助于防止自身免疫反应。

据了解，cGAS感知细胞质中微生物和自身的DNA，以激活免疫应答和炎症。cGAS还与染色质相关，尤其是当细胞进入有丝分裂周期核被膜破裂后。 尚不清楚细胞周期过渡期间如何调控cGAS。

附：英文原文

Title: Phosphorylation and chromatin tethering prevent cGAS activation during mitosis

Author: Tuo Li, Tuozhi Huang, Mingjian Du, Xiang Chen, Fenghe Du, Junyao Ren, Zhijian J. Chen

Issue&Volume: 2021/02/04

Abstract: The cyclic GMP-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, 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. Secondly, 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.

DOI: 10.1126/science.abc5386

Source: https://science.sciencemag.org/content/early/2021/02/03/science.abc5386