title: TRAF-interacting protein (TRIP) negatively regulates IFN-β production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1.
abstract: TANK-binding kinase 1 (TBK1) plays an essential role in Toll-like receptor (TLR)- and retinoic acid-inducible gene I (RIG-I)-mediated induction of type I interferon (IFN; IFN-α/β) and host antiviral responses. How TBK1 activity is negatively regulated remains largely unknown. We report that TNF receptor-associated factor (TRAF)-interacting protein (TRIP) promotes proteasomal degradation of TBK1 and inhibits TLR3/4- and RIG-I-induced IFN-β signaling. TRIP knockdown resulted in augmented activation of IFN regulatory factor 3 (IRF3) and enhanced expression of IFN-β in TLR3/4- and RIG-I-activated primary peritoneal macrophages, whereas overexpression of TRIP had opposite effects. Consistently, TRIP impaired Sendai virus (SeV) infection-induced IRF3 activation and IFN-β production and promoted vesicular stomatitis virus (VSV) replication. As an E3 ubiquitin ligase, TRIP negatively regulated the cellular levels of TBK1 by directly binding to and promoting K48-linked polyubiquitination of TBK1. Therefore, we identified TRIP as a negative regulator in TLR3/4- and RIG-I-triggered antiviral responses and suggested TRIP as a potential target for the intervention of diseases with uncontrolled IFN-β production.
authors.affiliation: Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Immunology, Shandong University School of Medicine, Shandong 250012, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Xueying
authors.initials: X
authors.lastname: Zhao
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Hong
authors.initials: H
authors.lastname: Meng
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Chengjiang
authors.initials: C
authors.lastname: Gao
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000821:virology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000097905:Roundabout Proteins
chemical_list: D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C498588:Tbk1 protein, mouse