Nuclear cGAS Functions Non-canonically to Enhance Antiviral Immunity via Recruiting Methyltransferase Prmt5

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. [Display omitted] •cGAS is essential for restricting RNA virus infection•Nuclear cGAS recruits Prmt5 upon virus infection•Prmt5 regulates histone arginine modification of IFN promoters•Prmt5 deficiency impairs the innate antiviral responses Cui et al. show that nuclear-localized cGAS recruits Prmt5 and facilitates Prmt5-mediated H3R2me2s modification at the promoters of type I IFNs, thus enhancing antiviral immunity upon RNA and DNA virus infections. This finding uncovers a non-canonical function of nuclear cGAS in innate immunity via regulating histone modification.