Identification of poly(ADP-ribose) polymerase 9 (PARP9) as a noncanonical sensor for RNA virus in dendritic cells

• Published in: Nature communications Vol. 12; no. 1; pp. 2681 - 17
• Main Authors: Xing, Junji, Zhang, Ao, Du, Yong, Fang, Mingli, Minze, Laurie J., Liu, Yong-Jun, Li, Xian Chang, Zhang, Zhiqiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/21; 13/31; 13/95; 14/19; 38/109; 38/91; 631/250; 631/250/262/2106; 64/60; 692/420/254; 692/699/255/2514; 82/80; 96/109; Adenosine diphosphate; Animals; Antiviral drugs; Chlorocebus aethiops; Dendritic cells; Dendritic Cells - enzymology; Dendritic Cells - virology; Humanities and Social Sciences; Humans; Immune system; Infections; Interferon; Interferon regulatory factor 3; Interferon regulatory factor 7; Interferon Regulatory Factor-3 - metabolism; Interferon Regulatory Factor-7 - metabolism; Interferon Type I - metabolism; Kinases; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria; multidisciplinary; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nucleic acids; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleic acid; Ribose; RNA; RNA Virus Infections - enzymology; RNA Virus Infections - virology; RNA viruses; RNA Viruses - genetics; RNA Viruses - physiology; RNA, Viral - metabolism; Science; Science (multidisciplinary); Sensors; Signal Transduction; THP-1 Cells; Vero Cells; Viral infections; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23003-4

Innate immune cells are critical in protective immunity against viral infections, involved in sensing foreign viral nucleic acids. Here we report that the poly(ADP-ribose) polymerase 9 (PARP9), a member of PARP family, serves as a non-canonical sensor for RNA virus to initiate and amplify type I interferon (IFN) production. We find knockdown or deletion of PARP9 in human or mouse dendritic cells and macrophages inhibits type I IFN production in response to double strand RNA stimulation or RNA virus infection. Furthermore, mice deficient for PARP9 show enhanced susceptibility to infections with RNA viruses because of the impaired type I IFN production. Mechanistically, we show that PARP9 recognizes and binds viral RNA, with resultant recruitment and activation of the phosphoinositide 3-kinase (PI3K) and AKT3 pathway, independent of mitochondrial antiviral-signaling (MAVS). PI3K/AKT3 then activates the IRF3 and IRF7 by phosphorylating IRF3 at Ser385 and IRF7 at Ser437/438 mediating type I IFN production. Together, we reveal a critical role for PARP9 as a non-canonical RNA sensor that depends on the PI3K/AKT3 pathway to produce type I IFN. These findings may have important clinical implications in controlling viral infections and viral-induced diseases by targeting PARP9. Innate immune cells play critical roles patrolling for and detecting viral infection by expression of a range of nucleic acid sensors. Here the authors implicate PARP9 in the detection of viral RNA and the induction of the IFN pathway via PI3K/AKT3.