title: Innate antiviral host defense attenuates TGF-β function through IRF3-mediated suppression of Smad signaling.
abstract: TGF-β signaling is essential in many processes, including immune surveillance, and its dysregulation controls various diseases, including cancer, fibrosis, and inflammation. Studying the innate host defense, which functions in most cell types, we found that RLR signaling represses TGF-β responses. This regulation is mediated by activated IRF3, using a dual mechanism of IRF3-directed suppression. Activated IRF3 interacts with Smad3, thus inhibiting TGF-β-induced Smad3 activation and, in the nucleus, disrupts functional Smad3 transcription complexes by competing with coregulators. Consequently, IRF3 activation by innate antiviral signaling represses TGF-β-induced growth inhibition, gene regulation and epithelial-mesenchymal transition, and the generation of Treg effector lymphocytes from naive CD4(+) lymphocytes. Conversely, silencing IRF3 expression enhances epithelial-mesenchymal transition, TGF-β-induced Treg cell differentiation upon virus infection, and Treg cell generation in vivo. We present a mechanism of regulation of TGF-β signaling by the antiviral defense, with evidence for its role in immune tolerance and cancer cell behavior.
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Cell and Tissue Biology, University of California at San Francisco, CA 94143, USA. Electronic address: xupl@zju.edu.cn.
authors.forename: Pinglong
authors.initials: P
authors.lastname: Xu
authors.affiliation: Diabetes Center and the Department of Medicine, University of California at San Francisco, CA 94143, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Bailey-Bucktrout
authors.affiliation: Department of Medicine and Cardiovascular Research Institute, University of California at San Francisco, CA 94143, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Diabetes Center and the Department of Medicine, University of California at San Francisco, CA 94143, USA.
authors.forename: Daqi
authors.initials: D
authors.lastname: Xu
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Cell and Tissue Biology, University of California at San Francisco, CA 94143, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Du
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Cell and Tissue Biology, University of California at San Francisco, CA 94143, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Liu
authors.affiliation: Lung Biology Center and the Department of Medicine, University of California at San Francisco, CA 94143, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Melton
authors.affiliation: Lung Biology Center and the Department of Medicine, University of California at San Francisco, CA 94143, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.affiliation: Department of Medicine and Cardiovascular Research Institute, University of California at San Francisco, CA 94143, USA.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Chapman
authors.affiliation: Diabetes Center and the Department of Medicine, University of California at San Francisco, CA 94143, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Cell and Tissue Biology, University of California at San Francisco, CA 94143, USA. Electronic address: rik.derynck@ucsf.edu.
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D058750:Epithelial-Mesenchymal Transition; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D008810:Mice, Inbred C57BL; D029082:Sendai virus / Q000276:immunology*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta