State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, China.
Division of Immunology, Department of Pediatrics, The Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2020 Dec 8;33(10):108490. doi: 10.1016/j.celrep.2020.108490.
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.
环鸟苷酸-腺苷酸合酶（cGAS）在感知细胞溶质 DNA 后，催化产生环鸟苷酸-腺苷酸单磷酸（cGAMP），从而激活 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在很大程度上仍然未知。在这里，我们报告细胞核中的 cGAS 对于诱导 RNA/DNA 病毒触发的细胞因子和趋化因子是必不可少的。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可有可无的。cGAS 缺乏并不影响双链 RNA（dsRNA）诱导的 IRF3 的磷酸化、二聚化或核易位。在机制上，核定位的 cGAS 与蛋白精氨酸甲基转移酶 5（Prmt5）相互作用，Prmt5 催化 IFNb 和 Ifna4 启动子上组蛋白 H3 精氨酸 2 的对称二甲基化，从而促进 IRF3 的进入。Prmt5 的缺乏或破坏其催化活性会抑制 I 型干扰素（IFNs）的产生，从而损害宿主对 RNA/DNA 病毒感染的防御能力。总之，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经典功能。
