TY - JOUR
T1 - Cbl-b mediates TGFβ sensitivity by downregulating inhibitory SMAD7 in primary T cells
AU - Gruber, Thomas
AU - Hinterleitner, Reinhard
AU - Hermann-Kleiter, Natascha
AU - Meisel, Marlies
AU - Kleiter, Ingo
AU - Wang, Chiuhui Mary
AU - Viola, Antonella
AU - Pfeifhofer-Obermair, Christa
AU - Baier, Gottfried
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
KW - Cbl-b
KW - SMAD
KW - TGFβ signaling
UR - http://www.scopus.com/inward/record.url?scp=84890413258&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890413258&partnerID=8YFLogxK
U2 - 10.1093/jmcb/mjt017
DO - 10.1093/jmcb/mjt017
M3 - Article
C2 - 23709694
AN - SCOPUS:84890413258
VL - 5
SP - 358
EP - 368
JO - Journal of Molecular Cell Biology
JF - Journal of Molecular Cell Biology
SN - 1674-2788
IS - 6
ER -