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.

Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells / T. Gruber, R. Hinterleitner, N. Hermann-Kleiter, M. Meisel, I. Kleiter, C.M. Wang, A. Viola, C. Pfeifhofer-Obermair, G. Baier. - In: JOURNAL OF MOLECULAR CELL BIOLOGY. - ISSN 1674-2788. - 5:6(2013 Jun 26), pp. 358-368. [Epub ahead of print] [10.1093/jmcb/mjt017]

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

A. Viola;
2013

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.
Cbl-b ; SMAD ; TGFβ signaling
Settore MED/04 - Patologia Generale
26-giu-2013
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/226443
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