Department for Pharmacology and Genetics, Medical University of Innsbruck, Innsbruck, Austria.
J Mol Cell Biol. 2013 Dec;5(6):358-68. doi: 10.1093/jmcb/mjt017. Epub 2013 May 24.
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.
T 细胞内转化生长因子 β（TGFβ）受体信号转导对于控制免疫反应起着至关重要的作用。已经表明 RING 型 E3 连接酶 Cbl-b 介导 T 细胞对 TGFβ 的敏感性；然而，这一过程的机制尚不清楚。本研究表明，SMAD7，TGFβ 受体（TGFβR）信号的既定负调控因子，是 Cbl-b 的关键下游效应靶标。SMAD7 蛋白水平而非 SMAD7 mRNA 水平在 cblb(-/-)T 细胞中上调。Cbl-b 直接与 SMAD7 相互作用并泛素化 SMAD7，表明 Cbl-b 在后转录水平调节 SMAD7。为了支持这一观点，在 cblb(-/-) 小鼠中同时遗传缺失 SMAD7 恢复了 T 细胞细胞因子反应对 TGFβ 的敏感性，并消除了 cblb(-/-) 小鼠的肿瘤排斥表型。这些结果表明，Cbl-b 在体外和体内 T 细胞反应中通过直接靶向 SMAD7 进行降解来控制 TGFβR 信号转导方面发挥着重要的、非冗余的作用。
