E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity.
E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity.
复制标题
DOI：
10.1016/j.celrep.2012.04.008
复制
发表时间：
2012-05-31
期刊：
影响因子：
8.8
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Guo H;Qiao G;Ying H;Li Z;Zhao Y;Liang Y;Yang L;Lipkowitz S;Penninger JM;Langdon WY;Zhang J
E3泛素连接酶Cbl-b在T细胞活化和耐受诱导中起关键作用。然而，Cbl-b抑制T细胞活化的分子机制仍不清楚。在这里，我们报告，Cbl-b不抑制PI 3-K，而是抑制TCR/CD 28诱导的Pten失活。因此，Cbl-b−/− T细胞中Akt活性的升高是由于Pten失活的增强。Cbl-b抑制T细胞中Pten失活是通过阻止Pten与Nedd 4的结合来实现的，Nedd 4靶向Pten K13进行K63连接的多聚泛素化。与这一发现一致，将Nedd 4缺陷引入Cbl-b−/−小鼠消除了由Cbl-b缺失引起的超T细胞反应。因此，我们的数据是第一个证明，Cbl-b抑制T细胞活化抑制Pten失活独立于其泛素连接酶活性。
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 PI3-K, 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 are the first to demonstrate that Cbl-b inhibits T cell activation by suppressing Pten inactivation independently of its ubiquitin ligase activity.
登录
查看更多内容
DOI：
10.1073/pnas.0803233105
发表时间：
2008-06-24
影响因子：
11.1
作者：
Fouladkou, Fatemeh;Landry, Tamara;Rotin, Daniela
通讯作者：
Rotin, Daniela
DOI：
10.1073/pnas.0908899107
发表时间：
2010-03-23
影响因子：
11.1
作者：
Chagpar, Ryaz B.;Links, Philip H.;Anderson, Deborah H.
通讯作者：
Anderson, Deborah H.
影响因子：
3.6
作者：
Oksvold, Morten P.;Dagger, Samantha A.;Langdon, Wallace Y.
通讯作者：
Langdon, Wallace Y.
影响因子：
32.4
作者：
Jeon, MS;Atfield, A;Penninger, JM
通讯作者：
Penninger, JM
影响因子：
4.8
作者：
Pages, F;Ragueneau, M;Olive, D
通讯作者：
Olive, D