PCBP2 maintains antiviral signaling homeostasis by regulating cGAS enzymatic activity via antagonizing its condensation

Cyclic GMP-AMP synthase (cGAS) plays a major role in detecting pathogenic DNA. It produces cyclic dinucleotide cGAMP, which subsequently binds to the adaptor protein STING and further triggers antiviral innate immune responses. However, the molecular mechanisms regulating cGAS enzyme activity remain largely unknown. Here, we characterize the cGAS-interacting protein Poly(rC)-binding protein 2 (PCBP2), which plays an important role in controlling cGAS enzyme activity, thereby mediating appropriate cGAS-STING signaling transduction. We found that PCBP2 overexpression reduced cGAS-STING antiviral signaling, whereas loss of PCBP2 significantly increased cGAS activity. Mechanistically, we showed that PCBP2 negatively regulated anti-DNA viral signaling by specifically interacting with cGAS but not other components. Moreover, PCBP2 inhibited cGAS enzyme activity by antagonizing cGAS condensation, thus ensuring the normal production of cGAMP and balancing cGAS-STING signal transduction. Collectively, our findings provide novel insight into mechanisms regulating cGAS-mediated antiviral innate immune signaling.