Shandong Provincial Key Laboratory of Infection and Immunology, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Department of Geriatric Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China.
Sci Adv. 2021 Mar 24;7(13). doi: 10.1126/sciadv.abc1834. Print 2021 Mar.
Cyclic GMP-AMP synthase (cGAS) functions as an essential DNA sensor, which senses the cytoplasmic double-stranded DNA and activates the antiviral response. However, the posttranslational modification of cGAS remains to be fully understood and whether it has arginine methylation modification remains unknown. Here, we identified protein arginine methyltransferase 5 (PRMT5) as a direct binding partner of cGAS, and it catalyzed the arginine symmetrical dimethylation of cGAS at the Arg residue. Further investigation demonstrated that methylation of cGAS by PRMT5 attenuated cGAS-mediated antiviral immune response by blocking the DNA binding ability of cGAS. Oral administration of PRMT5 inhibitors significantly protected mice from HSV-1 infection and prolonged the survival time of these infected mice. Therefore, our findings revealed an essential regulatory effect of PRMT5 on cGAS-mediated antiviral immune response and provided a promising potential antiviral strategy by modulating PRMT5.
环鸟苷酸-腺苷酸合酶 (cGAS) 作为一种重要的 DNA 传感器，可感应细胞质中的双链 DNA 并激活抗病毒反应。然而，cGAS 的翻译后修饰仍有待充分了解，其是否存在精氨酸甲基化修饰尚不清楚。在这里，我们鉴定了蛋白精氨酸甲基转移酶 5（PRMT5）为 cGAS 的直接结合伴侣，它催化 cGAS 在精氨酸残基上的精氨酸对称二甲基化。进一步的研究表明，PRMT5 对 cGAS 的甲基化通过阻断 cGAS 的 DNA 结合能力来减弱 cGAS 介导的抗病毒免疫反应。PRMT5 抑制剂的口服给药可显著保护小鼠免受 HSV-1 感染，并延长感染这些小鼠的存活时间。因此，我们的研究结果揭示了 PRMT5 对 cGAS 介导的抗病毒免疫反应的重要调节作用，并通过调节 PRMT5 提供了一种有前途的潜在抗病毒策略。
