Arginine methyltransferase PRMT5 negatively regulates cGAS-mediated antiviral immune response

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(124) 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.

Automated summary

PRMT5 catalyzes arginine symmetrical dimethylation of cGAS, attenuating the antiviral immune response by blocking cGAS' DNA binding ability. Inhibitors of PRMT5 protect mice from HSV-1 infection and prolong their survival time, indicating the potential of modulating PRMT5 as an antiviral strategy.