Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS

Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases. [Display omitted] •DNA damage induces the cytosolic translocation of PARP1 in an iNOS-dependent manner•DNA-PK phosphorylates PARP1 on Thr594 and instructs its cytosolic translocation•PARP1 PARylates human cGAS on D191 or mouse cGAS on E176 to terminate its DNA binding•PARP1-mediated PARylation of cGAS inhibits antiviral immunity Wang, Zhao, and Chang et al. uncovered a critical role for the canonical nuclear protein PARP1 in the cytosol by PARylating cyclic GMP-AMP synthase to inhibit host innate immunity, representing a beginning in the study of the function of cytosolic PARP1 in other biological processes.