PMID:22065573

Citation	Siednienko, J, Maratha, A, Yang, S, Mitkiewicz, M, Miggin, SM and Moynagh, PN (2011) Nuclear factor κB subunits RelB and cRel negatively regulate Toll-like receptor 3-mediated β-interferon production via induction of transcriptional repressor protein YY1. J. Biol. Chem. 286:44750-63
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.
Links	PubMed PMC3247990 Online version:10.1074/jbc.M111.250894
Keywords	Active Transport, Cell Nucleus/drug effects; Active Transport, Cell Nucleus/genetics; Cell Line, Tumor; Cell Nucleus/genetics; Cell Nucleus/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Gene Expression Regulation/drug effects; Gene Expression Regulation/genetics; HEK293 Cells; Humans; Interferon Inducers/pharmacology; Interferon Regulatory Factor-7/genetics; Interferon Regulatory Factor-7/metabolism; Interferon-beta/biosynthesis; Interferon-beta/genetics; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Poly I-C/pharmacology; Repressor Proteins/genetics; Repressor Proteins/metabolism; Toll-Like Receptor 3/biosynthesis; Toll-Like Receptor 3/genetics; Transcription Factor RelB/genetics; Transcription Factor RelB/metabolism; Virus Diseases/genetics; Virus Diseases/metabolism; YY1 Transcription Factor/genetics; YY1 Transcription Factor/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:TYY1	part_of	GO:0005634: nucleus	ECO:0000315: mutant phenotype evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:TYY1	involved_in	GO:0010629: negative regulation of gene expression	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:TYY1		GO:0032688: negative regulation of interferon-beta production	ECO:0000315:		P		Fig. 2DE, Fig. 5BC, and Fig. 6	complete CACAO 3240
HUMAN:TYY1		GO:0005634: nucleus	ECO:0000315:		C		Fig. 5A and Fig. 6C	complete CACAO 3241
HUMAN:TYY1		GO:0010629: negative regulation of gene expression	ECO:0000315:		P		Fig. 5CD	complete CACAO 3242
HUMAN:REL		GO:0032688: negative regulation of interferon-beta production	ECO:0000314:		P		Fig. 4	complete CACAO 3243
HUMAN:REL		GO:0005634: nucleus	ECO:0000315:		C		Fig. 3D	complete CACAO 3244
HUMAN:REL		GO:0010629: negative regulation of gene expression	ECO:0000314:		P		Fig. 4C	complete CACAO 3245
HUMAN:REL	involved_in	GO:0010629: negative regulation of gene expression	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:REL	part_of	GO:0005634: nucleus	ECO:0000315: mutant phenotype evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:REL	involved_in	GO:0032688: negative regulation of interferon-beta production	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:RELB		GO:0032688: negative regulation of interferon-beta production	ECO:0000315:		P		Fig. 4	complete CACAO 3246
HUMAN:RELB		GO:0005634: nucleus	ECO:0000314:		C		Fig. 3C	complete CACAO 3247
HUMAN:RELB	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:RELB	involved_in	GO:0032688: negative regulation of interferon-beta production	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:TF65		GO:0005634: nucleus	ECO:0000314:		C		Fig. 7A	complete CACAO 3237
HUMAN:TF65	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:IRF7		GO:0032728: positive regulation of interferon-beta production	ECO:0000315:		P		Fig. 7BC	complete CACAO 3235
HUMAN:IRF7		GO:0005634: nucleus	ECO:0000314:		C		Fig. 6D and Fig. 7A	complete CACAO 3236
HUMAN:IRF7	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:IRF7	involved_in	GO:0032728: positive regulation of interferon-beta production	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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