Nuclear cGAS Functions Non-canonically to Enhance Antiviral Immunity via Recruiting Methyltransferase Prmt5
Nuclear cGAS Functions Non-canonically to Enhance Antiviral Immunity via Recruiting Methyltransferase Prmt5
复制标题
核cGAS通过招募甲基转移酶Prmt5以非规范方式增强抗病毒免疫力
DOI：
10.1016/j.celrep.2020.108490
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发表时间：
2020-12-08
期刊：
影响因子：
8.8
通讯作者：
Wang, Chen
中科院分区：
文献类型：
--
作者：
Cui, Shufang;Yu, Qiuya;Wang, Chen
环鸟苷单磷酸(GMP)-AMP合成酶（cGAS）通过感知胞质DNA，催化产生环鸟苷单磷酸-腺苷单磷酸（cGAMP），激活STING-TBK1-IRF3信号通路。cGAS也存在于细胞核中，但相关的核功能或机制仍不清楚。在这里，我们报道核cGAS是诱导RNA/DNA病毒触发的细胞因子和趋化因子不可或缺的。出乎意料的是，cGAS的dna结合/核苷酸转移酶活性对于rna病毒诱导的基因表达是必不可少的。cGAS缺乏不影响双链RNA （dsRNA）诱导的IRF3的磷酸化、二聚化或核易位。机制上，核定位的cGAS与蛋白精氨酸甲基转移酶5 （Prmt5）相互作用，在Ifnb和Ifna4启动子处催化组蛋白H3精氨酸2的对称二甲基化，从而促进IRF3的进入。缺乏Prmt5或破坏其催化活性会抑制I型干扰素（ifn）的产生，从而削弱宿主对RNA/DNA病毒感染的防御能力。综上所述，我们的研究揭示了核定位的cGAS通过调节组蛋白精氨酸修饰在先天免疫中的非规范功能。
Cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS), upon sensing cytosolic DNA, catalyzes the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), which activates STING-TBK1-IRF3 signaling. cGAS is also present in the nucleus, but the relevant nuclear function or mechanism remains largely unknown. Here, we report that nuclear cGAS is indispensable for inducing cytokines and chemokines triggered by RNA/DNA viruses. Unexpectedly, the DNA-binding/nucleotidyltransferase activity of cGAS is dispensable for RNA-virus-induced genes expression. cGAS deficiency does not affect the phosphorylation, dimerization, or nuclear translocation of IRF3 induced by double-stranded RNA (dsRNA). Mechanistically, nuclear-localized cGAS interacts with protein arginine methyltransferase 5 (Prmt5), which catalyzes the symmetric dimethylation of histone H3 arginine 2 at Ifnb and Ifna4 promoters, thus facilitating the access of IRF3. Deficiency of Prmt5 or disrupting its catalytic activity suppresses the production of type I interferons (IFNs), impairing the host defenses against RNA/DNA virus infections. Taken together, our study uncovers a non-canonical function of nuclear-localized cGAS in innate immunity via regulating histone arginine modification.