E3 Ubiquitin Ligase Cbl-b Regulates Pten via Nedd4 in T Cells Independently of Its Ubiquitin Ligase Activity

被引：61

作者：

Guo, Hui ^{[1
]}

Qiao, Guilin ^{[1
,2
]}

Ying, Haiyan ^{[1
,2
]}

Li, Zhenping ^{[1
]}

Zhao, Yixia ^{[1
,2
]}

Liang, Yanran ^{[1
,2
]}

Yang, Lifen ^{[1
,2
]}

Lipkowitz, Stanley ^{[4
]}

Penninger, Josef M. ^{[5
]}

Langdon, Wallace Y. ^{[6
]}

Zhang, Jian ^{[1
,2
,3
]}

机构：

[1] Univ Chicago, Dept Med, Sect Nephrol, Chicago, IL 60637 USA

[2] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA

[3] Univ Chicago, Comm Mol Med, Chicago, IL 60637 USA

[4] NCI, Lab Cellular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[5] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria

[6] Univ Western Australia, Sch Pathol & Lab Med, Crawley, WA 6009, Australia

来源：

CELL REPORTS | 2012年 / 1卷 / 05期

基金：

美国国家卫生研究院;

关键词：

PHOSPHATIDYLINOSITOL; 3-KINASE; TUMOR SUPPRESSION; CUTTING EDGE; NEGATIVE REGULATION; CD28; COSTIMULATION; ACTIVATION; RECEPTOR; MICE; AUTOIMMUNITY; DEGRADATION;

D O I：

10.1016/j.celrep.2012.04.008

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：472 / 482

页数：11

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