title: An alternative splicing isoform of MITA antagonizes MITA-mediated induction of type I IFNs.
abstract: Mediator of IFN regulatory transcription factor 3 activation (MITA) is an important adaptor protein to mediate the induction of type I IFNs. In this study, we identified an alternatively spliced isoform of MITA lacking exon 7, termed MITA-related protein (MRP). MRP shares the N-terminal portion aa 1-253 with MITA but possesses a unique 30-aa sequence at the carboxyl terminal part, therefore lacking the conserved domains including TANK-binding kinase 1 (TBK1) and cyclic diguanylate binding domain. MRP is expressed in multiple tissues and distinct cell lines. Overexpression of MRP inhibited MITA-mediated activation of IFN-β promoter by sendai virus infection and cyclic diguanylate treatment but enhanced that in HSV-1 infection. Interestingly, MRP expression was reduced after Sendai virus infection but was upregulated after HSV-1 infection. Overexpression of MRP inhibited MITA-mediated induction of IFN-β via TBK1-IFN regulatory transcription factor 3 by disrupting the MITA-TBK1 interaction. However, NF-κB pathway was still activated by MRP, as MRP retained the ability to interact with inducible inhibitor of NF-κB (iκB) kinase. Thus, MRP acts as a dominant negative regulator of MITA-mediated induction of IFN production.
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China;
authors.forename: Honghe
authors.initials: H
authors.lastname: Chen
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Pei
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhu
authors.forename: Rui
authors.initials: R
authors.lastname: Zeng
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanyi
authors.initials: Y
authors.lastname: Wang
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.forename: Xinwen
authors.initials: X
authors.lastname: Chen
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D018259:Herpesvirus 1, Human / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D029082:Sendai virus / Q000502:physiology; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D006152:Cyclic GMP; D018076:DNA, Complementary; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid; C403191:TBK1 protein, human