Ku proteins promote DNA binding and condensation of cyclic GMP-AMP synthase.
Ku proteins promote DNA binding and condensation of cyclic GMP-AMP synthase.
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DOI：
10.1016/j.celrep.2022.111310
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发表时间：
2022-09
期刊：
影响因子：
8.8
通讯作者：
Xinyue Tao;Jiali Song;Ying-ying Song;Yao Zhang;Jing Yang;Pengfei Zhang;Dechong Zhang;Dahua Chen;Qinmiao Sun
中科院分区：
文献类型：
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作者：
Xinyue Tao;Jiali Song;Ying-ying Song;Yao Zhang;Jing Yang;Pengfei Zhang;Dechong Zhang;Dahua Chen;Qinmiao Sun
环状GMP-AMP合成酶(CGAS)是一种胞质DNA传感器，在调节抗病毒信号方面起着关键作用。CGAS与DNA结合并催化合成环状GMP-AMP(CGAMP)，cGAMP是下游信号转导所必需的。抗病毒反应是一个快速的生物学过程；然而，cGAS本身的DNA结合亲和力相对较低，这意味着cGAS-DNA复合体的形成需要一个额外的因子(S)来促进cGAS-DNA的结合，从而实现有效的抗病毒信号转导。在这里，我们报告了Ku蛋白(Ku80和Ku70)直接与cGAS相互作用，并正向调节cGAS介导的抗病毒信号。从机理上讲，我们发现Ku蛋白与cGAS的相互作用显著提高了cGAS与DNA的结合亲和力，并促进了cGAS在胞浆中的缩合，从而增强了cGAS的催化活性。我们的结果表明，Ku蛋白是cGAS在检测DNA病毒感染和确保有效的天然免疫信号转导方面的关键合作伙伴。
Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that plays a critical role in regulating antiviral signaling. cGAS binds to DNA and catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which is essential for downstream signal transduction. The antiviral response is a rapid biological process; however, cGAS itself has relatively low DNA binding affinity, implying that formation of the cGAS-DNA complex requires an additional factor(s) that promotes cGAS-DNA binding, allowing efficient antiviral signal transduction. Here, we report that the Ku proteins (Ku80 and Ku70) directly interact with cGAS and positively regulate cGAS-mediated antiviral signaling. Mechanistically, we find that the interaction of the Ku proteins with cGAS significantly increases the DNA-binding affinity of cGAS and promotes cGAS condensation in the cytosol, thereby enhancing cGAS catalytic activity. Our results show that the Ku proteins are critical partners of cGAS in sensing DNA virus infection and ensuring efficient innate immune signal transduction.