title: Transforming growth factor beta/Smad3 signaling regulates IRF-7 function and transcriptional activation of the beta interferon promoter.
abstract: The rapid induction of alpha interferon (IFN-alpha) and IFN-beta expression plays a critical role in the innate immune response against viral infection. We studied the effects of transforming growth factor beta (TGF-beta) and its intracellular effectors, the Smads, on the function of IRF-7, an essential transcription factor for IFN-alpha and -beta induction. IRF-7 interacted with Smads, and IRF-7, but not IRF-3, cooperated with Smad3 to activate IFN-beta transcription. This transcriptional cooperation occurred at the IRF-binding sequences in the IFN-beta promoter, and dominant-negative interference with TGF-beta receptor signaling and Smad3 function decreased IRF-7-mediated transcription. Furthermore, elimination of Smad3 expression in Smad3(-/-) fibroblasts delayed and decreased double-stranded RNA-induced expression of endogenous IFN-beta, whereas restoration of Smad3 expression enhanced IFN-beta induction. The IRF-7-Smad3 cooperativity resulted from the regulation of the transactivation activity of IRF-7 by Smad3, and dominant-negative interference with Smad3 function decreased IRF-7 activity. Consistent with the regulation by Smad3, the transcriptional activity of IRF-7 depended on and was regulated by TGF-beta signaling. Our studies underscore a role of TGF-beta/Smad3 signaling in IRF-7-mediated induction of IFN-beta expression.
authors.affiliation: Department of Growth and Development, Program in Cell Biology, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qing
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.forename: Lisa
authors.initials: L
authors.lastname: Choy
authors.forename: Rui-Yun
authors.initials: RY
authors.lastname: Wu
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Pagano
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
mesh_terms: D000818:Animals; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016899:Interferon-beta