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Mol Cell. 2014 Dec 18;56(6):723-37. doi: 10.1016/j.molcel.2014.11.027.

Innate antiviral host defense attenuates TGF-β function through IRF3-mediated suppression of Smad signaling.

Author information

1
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.
2
Diabetes Center and the Department of Medicine, University of California at San Francisco, CA 94143, USA.
3
Department of Medicine and Cardiovascular Research Institute, University of California at San Francisco, CA 94143, USA.
4
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.
5
Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China.
6
Lung Biology Center and the Department of Medicine, University of California at San Francisco, CA 94143, USA.
7
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.

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.

PMID:
25526531
PMCID:
PMC4273650
DOI:
10.1016/j.molcel.2014.11.027
[Indexed for MEDLINE]
Free PMC Article

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