E3 泛素连接酶 Cbl-b 通过 Nedd4 在 T 细胞中调节 Pten，而不依赖其泛素连接酶活性。
E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity.
机构信息
Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
出版信息
Cell Rep. 2012 May 31;1(5):472-82. doi: 10.1016/j.celrep.2012.04.008.
Abstract
E3 ubiquitin ligase Cbl-b plays a crucial role in T cell activation and tolerance induction. However, the molecular mechanism by which Cbl-b inhibits T cell activation remains unclear. Here, we report that Cbl-b does not inhibit PI3K but rather suppresses TCR/CD28-induced inactivation of Pten. The elevated Akt activity in Cbl-b(-/-) T cells is therefore due to heightened Pten inactivation. Suppression of Pten inactivation in T cells by Cbl-b is achieved by impeding the association of Pten with Nedd4, which targets Pten K13 for K63-linked polyubiquitination. Consistent with this finding, introducing Nedd4 deficiency into Cbl-b(-/-) mice abrogates hyper-T cell responses caused by the loss of Cbl-b. Hence, our data demonstrate that Cbl-b inhibits T cell activation by suppressing Pten inactivation independently of its ubiquitin ligase activity.
摘要
E3 泛素连接酶 Cbl-b 在 T 细胞激活和诱导耐受中发挥着关键作用。然而，Cbl-b 抑制 T 细胞激活的分子机制尚不清楚。在这里，我们报告 Cbl-b 不抑制 PI3K，而是抑制 TCR/CD28 诱导的 Pten 失活。因此，Cbl-b(-/-)T 细胞中 Akt 活性的升高是由于 Pten 失活加剧所致。Cbl-b 通过阻碍 Pten 与 Nedd4 的结合来抑制 T 细胞中 Pten 失活，Nedd4 将 Pten K13 靶向进行 K63 连接多泛素化。与这一发现一致的是，将 Nedd4 缺陷引入 Cbl-b(-/-)小鼠中会消除 Cbl-b 缺失引起的 T 细胞过度反应。因此，我们的数据表明，Cbl-b 通过抑制 Pten 失活来抑制 T 细胞激活，而不依赖于其泛素连接酶活性。
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