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 find that PCBP2 overexpression reduces cGAS-
STING antiviral signaling, whereas loss of PCBP2 significantly increases cGAS activity. Mechanistically, we show that PCBP2 negatively regulates anti-
DNA viral signaling by specifically interacting with cGAS but not other components. Moreover, PCBP2 decreases cGAS
enzyme activity by antagonizing cGAS condensation, thus ensuring the appropriate production of
cGAMP and balancing cGAS-
STING signal transduction. Collectively, our findings provide insight into how the cGAS-mediated
antiviral signaling is regulated.