MIP-T3 is a negative regulator of innate type I IFN response

J Immunol. 2011 Dec 15;187(12):6473-82. doi: 10.4049/jimmunol.1100719. Epub 2011 Nov 11.


TNFR-associated factor (TRAF) 3 is an important adaptor that transmits upstream activation signals to protein kinases that phosphorylate transcription factors to induce the production of type I IFNs, the important effectors in innate antiviral immune response. MIP-T3 interacts specifically with TRAF3, but its function in innate IFN response remains unclear. In this study, we demonstrated a negative regulatory role of MIP-T3 in type I IFN production. Overexpression of MIP-T3 inhibited RIG-I-, MDA5-, VISA-, TBK1-, and IKKε-induced transcriptional activity mediated by IFN-stimulated response elements and IFN-β promoter. MIP-T3 interacted with TRAF3 and perturbed in a dose-dependent manner the formation of functional complexes of TRAF3 with VISA, TBK1, IKKε, and IFN regulatory factor 3. Consistent with this finding, retinoic acid-inducible gene I- and TBK1-induced phosphorylation of IFN regulatory factor 3 was significantly diminished when MIP-T3 was overexpressed. Depletion of MIP-T3 facilitated Sendai virus-induced activation of IFN production and attenuated the replication of vesicular stomatitis virus. In addition, MIP-T3 was found to be dissociated from TRAF3 during the course of Sendai virus infection. Our findings suggest that MIP-T3 functions as a negative regulator of innate IFN response by preventing TRAF3 from forming protein complexes with critical downstream transducers and effectors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • Down-Regulation / genetics
  • Down-Regulation / immunology*
  • HEK293 Cells
  • Humans
  • Immunity, Innate* / genetics
  • Interferon Type I / antagonists & inhibitors*
  • Interferon Type I / biosynthesis
  • Interferon-beta / genetics
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology*
  • Promoter Regions, Genetic / immunology
  • Protein Binding / immunology
  • Respirovirus Infections / immunology
  • Respirovirus Infections / metabolism
  • Respirovirus Infections / virology
  • Sendai virus / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • TNF Receptor-Associated Factor 3 / antagonists & inhibitors
  • TNF Receptor-Associated Factor 3 / metabolism
  • Vero Cells


  • Interferon Type I
  • Microtubule-Associated Proteins
  • TNF Receptor-Associated Factor 3
  • TRAF3 protein, human
  • TRAF3IP1 protein, human
  • Interferon-beta