title: IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1.
abstract: Intracellular RNA viruses are sensed by receptors retinoic acid-inducible gene I/MDA5, which trigger formation of the mitochondrial antiviral signaling (MAVS) complex on mitochondria. Consequently, this leads to the activation of TNFR-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) and phosphorylation of IFN regulatory factor 3 (IRF3). It remains to be elucidated how MAVS activates TBK1/IRF3. In this study, we report that IFN-induced protein with tetratricopeptide repeats 3 (IFIT3) is significantly induced upon RNA virus infection. Ectopic expression or knockdown of IFIT3 could, respectively, enhance or impair IRF3-mediated gene expression. Mechanistically, the tetratrico-peptide repeat motif (E164/E165) of IFIT3 interacts with the N terminus (K38) of TBK1, thus bridging TBK1 to MAVS on the mitochondrion. Disruption of this interaction markedly attenuates the activation of TBK1 and IRF3. Furthermore, host antiviral responses are significantly boosted or crippled in the presence or absence of IFIT3. Collectively, our study characterizes IFIT3 as an important modulator in innate immunity, revealing a new function of the IFIT family proteins (IFN-induced protein with tetratricopeptide repeats).
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xin-Yi
authors.initials: XY
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Shan
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D012327:RNA Virus Infections / Q000276:immunology; D012328:RNA Viruses / Q000276:immunology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C116468:IFIT3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C505371:MAVS protein, human; D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human