Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Cell Rep. 2012 May 31;1(5):472-82. doi: 10.1016/j.celrep.2012.04.008.
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.
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。
