title: MIP-T3 is a negative regulator of innate type I IFN response.
abstract: 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.
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Ming-Him James
authors.initials: MH
authors.lastname: Ng
authors.forename: Ting-Hin
authors.initials: TH
authors.lastname: Ho
authors.forename: Kin-Hang
authors.initials: KH
authors.lastname: Kok
authors.forename: Kam-Leung
authors.initials: KL
authors.lastname: Siu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016899:Interferon-beta / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D010253:Respirovirus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014709:Vero Cells
chemical_list: D007370:Interferon Type I; D008869:Microtubule-Associated Proteins; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; C412724:TRAF3IP1 protein, human; D016899:Interferon-beta