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

作者：Fei Wang, Mengmeng Zhao, Boran Chang, Yilong Zhou, Xiangyang Wu, Mingtong Ma, Siyu Liu, Yajuan Cao, Mengge Zheng, Yifang Dang, Junfang Xu, Li Chen, Tianhao Liu, F. Tang, Yefei Ren, Zhu Xu, Z. Mao, Kai Huang, Min Luo, Jingsong Li, Haipeng Liu, Baoxue Ge · 发表于：Molecules and Cells · 年份：2022 · DOI：10.1016/j.molcel.2022.03.034 · 被引用次数：73 · 研究领域：Medicine

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.