Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS
Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS
复制标题
细胞质 PARP1 通过 PARylating cGAS 将基因组不稳定性与抗病毒免疫抑制联系起来。
DOI：
10.1016/j.molcel.2022.03.034
复制
发表时间：
2022-06-02
期刊：
影响因子：
16
通讯作者：
Ge, Baoxue
中科院分区：
文献类型：
--
作者：
Wang, Fei;Zhao, Mengmeng;Ge, Baoxue
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 Thr(594), 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 Asp(191) 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.
