1. Cbl-b mediates TGF sensitivity by downregulating inhibitory SMAD7 in primary T cells
- Author
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Natascha Hermann-Kleiter, Chiuhui Mary Wang, Thomas Gruber, Antonella Viola, Ingo Kleiter, Marlies Meisel, Reinhard Hinterleitner, Gottfried Baier, and Christa Pfeifhofer-Obermair
- Subjects
Chromatin Immunoprecipitation ,Knockout ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Cellular differentiation ,Smad7 Protein ,Interferon-gamma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Transforming Growth Factor beta ,Genetics ,medicine ,Animals ,Cbl-b ,SMAD ,TGFβ signaling ,Adaptor Proteins, Signal Transducing ,Cell Differentiation ,Mice, Knockout ,Microscopy, Confocal ,Proto-Oncogene Proteins c-cbl ,T-Box Domain Proteins ,Ubiquitination ,Medicine (all) ,Molecular Biology ,Cell Biology ,030304 developmental biology ,Microscopy ,0303 health sciences ,integumentary system ,biology ,Chemistry ,Signal Transducing ,Adaptor Proteins ,General Medicine ,Transforming growth factor beta ,Cell biology ,Ubiquitin ligase ,Cytokine ,medicine.anatomical_structure ,Confocal ,biology.protein ,CBLB ,Signal transduction ,030215 immunology ,Transforming growth factor - 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.
- Published
- 2013
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