Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells

J Mol Cell Biol. 2013 Dec;5(6):358-68. doi: 10.1093/jmcb/mjt017. Epub 2013 May 24.

Abstract

T cell-intrinsic transforming growth factor β (TGFβ) receptor signaling plays an essential role in controlling immune responses. The RING-type E3 ligase Cbl-b has been shown to mediate the sensitivity of T cells to TGFβ; however, the mechanism underlying this process is unknown. This study shows that SMAD7, an established negative regulator of TGFβ receptor (TGFβR) signaling, is a key downstream effector target of Cbl-b. SMAD7 protein levels, but not SMAD7 mRNA levels, are upregulated in cblb(-/-) T cells. Cbl-b directly interacts with and ubiquitinates SMAD7, suggesting that Cbl-b posttranscriptionally regulates SMAD7. In support of this notion, concomitant genetic loss of SMAD7 in cblb(-/-) mice restored TGFβ sensitivity on T cell cytokine responses and abrogated the tumor rejection phenotype of cblb(-/-) mice. These results demonstrate an essential and non-redundant role for Cbl-b in controlling TGFβR signaling by directly targeting SMAD7 for degradation during T cell responses in vitro and in vivo.

Keywords: Cbl-b; SMAD; TGFβ signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Chromatin Immunoprecipitation
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / metabolism*
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Cblb protein, mouse
  • Smad7 Protein
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transforming Growth Factor beta
  • Interferon-gamma
  • Proto-Oncogene Proteins c-cbl