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

Nat Commun. 2020 May 4;11(1):2193. doi: 10.1038/s41467-020-16014-0.

Meng Deng ¹ ² ³, Jason W Tam ² ⁴, Lufei Wang ¹, Kaixin Liang ¹ ², Sirui Li ² ⁴, Lu Zhang ² ⁵, Haitao Guo ² ⁴, Xiaobo Luo ⁶, Yang Zhang ⁷, Alex Petrucelli ² ⁴, Beckley K Davis ⁸, Brian J Conti ² ⁹, W June Brickey ² ¹⁰, Ching-Chang Ko ¹ ³, Yu L Lei ⁶, Shaocong Sun ¹¹, Jenny P-Y Ting ¹² ¹³ ¹⁴ ¹⁵

Affiliations

1 Oral and Craniofacial Biomedicine PhD Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
3 Department of Craniofacial and Surgery Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
4 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
5 Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27710, USA.
6 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48105, USA.
7 Department of Dermatology, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
8 Department of Biology, Franklin and Marshall College, Lancaster, PA, 17604, USA.
9 Biotechnology Center, University of Wisconsin-Madison, Madison, WI, 53706, USA.
10 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
11 Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
12 Oral and Craniofacial Biomedicine PhD Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA. Jenny_ting@med.unc.edu.
13 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA. Jenny_ting@med.unc.edu.
14 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA. Jenny_ting@med.unc.edu.
15 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA. Jenny_ting@med.unc.edu.

PMID: 32366851 DOI: 10.1038/s41467-020-16014-0

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.

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