2. Academic Validation
  3. 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

  • Mol Cell. 2022 Jun 2;82(11):2032-2049.e7. doi: 10.1016/j.molcel.2022.03.034.
Fei Wang 1,  Mengmeng Zhao 1,  Boran Chang 2,  Yilong Zhou 3,  Xiangyang Wu 4,  Mingtong Ma 3,  Siyu Liu 3,  Yajuan Cao 4,  Mengge Zheng 4,  Yifang Dang 4,  Junfang Xu 5,  Li Chen 6,  Tianhao Liu 6,  Fen Tang 3,  Yefei Ren 7,  Zhu Xu 8,  Zhiyong Mao 8,  Kai Huang 9,  Minhua Luo 10,  Jinsong Li 11,  Haipeng Liu 12,  Baoxue Ge 13
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200072, China; Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 2 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200072, China.
  • 4 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 5 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 6 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University School of Medicine, Shanghai 200433, China.
  • 7 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200072, China.
  • 8 Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 9 Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Clinical Center for Human Genomic Research, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 10 State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
  • 11 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: jsli@sibcb.ac.cn.
  • 12 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200072, China; Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: haipengliu@tongji.edu.cn.
  • 13 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200072, China; Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: baoxue_ge@tongji.edu.cn.
PMID: 35460603 DOI: 10.1016/j.molcel.2022.03.034
Abstract

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.

Keywords

DNA damage response; DNA-dependent protein kinase; PARylation; antiviral immunity; cyclic GMP-AMP synthase; inducible nitric oxide synthase; poly(ADP-ribose) polymerase 1; type I interferon.

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