TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination

• Published in: Nature communications Vol. 11; no. 1; p. 2193
• Main Authors: Deng, Meng, Tam, Jason W., Wang, Lufei, Liang, Kaixin, Li, Sirui, Zhang, Lu, Guo, Haitao, Luo, Xiaobo, Zhang, Yang, Petrucelli, Alex, Davis, Beckley K., Conti, Brian J., June Brickey, W., Ko, Ching-Chang, Lei, Yu L., Sun, Shaocong, Ting, Jenny P. -Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/89; 14; 14/19; 38; 38/39; 38/77; 42; 42/44; 45; 49; 631/250; 631/250/255; 631/250/262; 692/699; 692/699/255; Animals; Antiviral agents; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cells, Cultured; Chlorocebus aethiops; Cytosol - metabolism; Cytosol - virology; Double-stranded RNA; Gene deletion; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Immune system; Immunity; Inflammatory diseases; Innate immunity; Interferon; Interferon regulatory factor 3; Interferon Type I - genetics; Interferon Type I - metabolism; Jurkat Cells; Kinases; Lysine - genetics; Lysine - metabolism; Macrophages; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondria; multidisciplinary; Myeloid cells; Myeloid Cells - metabolism; Myeloid Cells - virology; Nucleic acids; Pattern recognition; Pattern recognition receptors; Polyinosinic:polycytidylic acid; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Receptors; Retinoic acid; Ribonucleic acid; RNA; RNA viruses; RNA, Viral - genetics; RNA, Viral - metabolism; Science; Science (multidisciplinary); Signal transduction; Signaling; Stomatitis; THP-1 Cells; Ubiquitination; Vero Cells; Vesicular stomatitis Indiana virus - genetics; Vesicular stomatitis Indiana virus - physiology; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16014-0

Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also well-expressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5’ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3 −/− primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells. RNA viruses can be detected by immune cell pattern recognition receptors, such as RLRs, resulting in MAVS-TBK1-IRF3 signalling and production of antiviral type 1 interferons. Here the authors show that macrophage TRAF3-interacting protein 3 regulates this signalling pathway by interacting with TRAF3 and TBK1 to suppress interferon responses.