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.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cytosol / metabolism
  • Cytosol / virology
  • Gene Expression Regulation*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Interferon Type I / genetics*
  • Interferon Type I / metabolism
  • Jurkat Cells
  • Lysine / genetics
  • Lysine / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / metabolism*
  • Myeloid Cells / virology
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Viral / genetics*
  • RNA, Viral / metabolism
  • THP-1 Cells
  • Ubiquitination
  • Vero Cells
  • Vesicular stomatitis Indiana virus / genetics
  • Vesicular stomatitis Indiana virus / physiology


  • Carrier Proteins
  • Interferon Type I
  • Membrane Proteins
  • RNA, Viral
  • TRAF3IP3 protein, mouse
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Lysine