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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation
  • Epithelial-Mesenchymal Transition
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / physiology*
  • Mice, Inbred C57BL
  • Sendai virus / immunology*
  • Signal Transduction
  • Smad3 Protein / metabolism*
  • T-Lymphocytes, Regulatory / immunology
  • Transcription, Genetic
  • Transcriptional Activation / immunology
  • Transforming Growth Factor beta / physiology*


  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta