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

Hui Guo | Zendy; Guilin Qiao | Zendy; Haiyan Ying | Zendy; Zhenping Li | Zendy; Yixia Zhao | Zendy; Yanran Liang | Zendy; Lifen Yang | Zendy; Stanley Lipkowitz | Zendy; Josef Penninger | Zendy; Wallace Y. Langdon | Zendy; Jian Zhang | Zendy

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

Author(s) -

Hui Guo,

Guilin Qiao,

Haiyan Ying,

Zhenping Li,

Yixia Zhao,

Yanran Liang,

Lifen Yang,

Stanley Lipkowitz,

Josef Penninger,

Wallace Y. Langdon,

Jian Zhang

Publication year - 2012

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2012.04.008

Subject(s) - ubiquitin ligase , nedd4 , ubiquitin , dna ligase , pten , microbiology and biotechnology , ubiquitin protein ligases , chemistry , biology , biochemistry , signal transduction , pi3k/akt/mtor pathway , enzyme , gene

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.

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