Regulation of cGAS activity by RNA-modulated phase separation.

ABSTRACT: Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA (dsDNA) sensor that functions in the innate immune system. Upon binding dsDNA, cGAS and dsDNA form phase-separated condensates in which cGAS catalyzes the synthesis of 2'3'-cyclic GMP-AMP that subsequently triggers a STING-dependent, type I interferon (IFN-I) response. Here, we show that cytoplasmic RNAs regulate cGAS activity. We discover that RNAs do not activate cGAS but rather promote phase separation of cGAS in vitro. In cells, cGAS colocalizes with RNA and forms complexes with RNA. In the presence of cytoplasmic dsDNA, RNAs colocalize with phase-separated condensates of cGAS and dsDNA. Further in vitro assays showed that RNAs promote the formation of cGAS-containing phase separations and enhance cGAS activity when the dsDNA conc

SUBMITTER: Chen S 

PROVIDER: S-EPMC9900338 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature