title: Nuclear factor κB subunits RelB and cRel negatively regulate Toll-like receptor 3-mediated β-interferon production via induction of transcriptional repressor protein YY1.
abstract: The induction of β-interferon (IFN-β) is a key anti-viral response to infection by RNA viruses. Virus-induced expression of IFN-β requires the co-operative action of the transcription factors IRF-3/7, NF-κB, and ATF-2/c-Jun on the IFN-β promoter leading to the orderly recruitment of chromatin remodeling complexes. Although viruses strongly activate NF-κB and promote its binding to the IFN-β promoter, recent studies have indicated that NF-κB is not essential for virus-induced expression of IFN-β. Herein, we examined the role of NF-κB in regulating IFN-β expression in response to the viral-sensing Toll-like receptor 3 (TLR3). Intriguingly pharmacological inhibition of the NF-κB pathway augments late phase expression of IFN-β expression in response to TLR3 stimulation. We show that the negative effect of NF-κB on IFN-β expression is dependent on the induction of the transcriptional repressor protein YinYang1. We demonstrate that the TLR3 ligand polyriboinosinic:polyribocytidylic acid (poly(I:C)) induces expression and nuclear translocation of YinYang1 where it interacts with the IFN-β promoter and inhibits the binding of IRF7 to the latter. Evidence is also presented showing that the NF-κB subunits c-Rel and RelB are the likely key drivers of these negative effects on IFN-β expression. These findings thus highlight for the first time a novel self-regulatory mechanism that is employed by TLR3 to limit the level and duration of IFN-β expression.
authors: Institute of Immunology, National University of Ireland Maynooth, County Kildare, Ireland.
authors: Jakub
authors: J
authors: Siednienko
authors: Ashwini
authors: A
authors: Maratha
authors: Shuo
authors: S
authors: Yang
authors: Malgorzata
authors: M
authors: Mitkiewicz
authors: Sinéad M
authors: SM
authors: Miggin
authors: Paul N
authors: PN
authors: Moynagh
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D020569:Proto-Oncogene Proteins c-rel; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis* / Q000235:genetics; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*; D014777:Virus Diseases / Q000235:genetics / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D007369:Interferon Inducers; D050839:Interferon Regulatory Factor-7; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel; C068059:REL protein, human; C497593:RELB protein, human; D012097:Repressor Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D051841:Transcription Factor RelB; D016899:Interferon-beta; D011070:Poly I-C