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

Meng Deng, Jason W. Tam, Lufei Wang, Kaixin Liang, Sirui Li, Lu Zhang, Haitao Guo, Xiaobo Luo, Yang Zhang, Alex Petrucelli, Beckley K. Davis, Brian J. Conti, W. June Brickey, Ching-Chang Ko, Yu L. Lei, Shaocong Sun and Jenny P. -Y. Ting ()
Additional contact information
Meng Deng: University of North Carolina at Chapel Hill
Jason W. Tam: University of North Carolina at Chapel Hill
Lufei Wang: University of North Carolina at Chapel Hill
Kaixin Liang: University of North Carolina at Chapel Hill
Sirui Li: University of North Carolina at Chapel Hill
Lu Zhang: University of North Carolina at Chapel Hill
Haitao Guo: University of North Carolina at Chapel Hill
Xiaobo Luo: University of Michigan School of Dentistry, University of Michigan Rogel Cancer Center, University of Michigan
Yang Zhang: Xi’an Jiaotong University
Alex Petrucelli: University of North Carolina at Chapel Hill
Beckley K. Davis: Franklin and Marshall College
Brian J. Conti: University of North Carolina at Chapel Hill
W. June Brickey: University of North Carolina at Chapel Hill
Ching-Chang Ko: University of North Carolina at Chapel Hill
Yu L. Lei: University of Michigan School of Dentistry, University of Michigan Rogel Cancer Center, University of Michigan
Shaocong Sun: The University of Texas MD Anderson Cancer Center
Jenny P. -Y. Ting: University of North Carolina at Chapel Hill

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16014-0

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