Journal article
E3 Ubiquitin Ligase Cbl-b Regulates Pten via Nedd4 in T Cells Independently of Its Ubiquitin Ligase Activity
Cell reports (Cambridge), Vol.1(5), pp.472-482
05/31/2012
DOI: 10.1016/j.celrep.2012.04.008
PMCID: PMC3387815
PMID: 22763434
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.
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► Cbl-b inhibits TCR-induced Akt activation in T cells ► This process is not due to the suppression of PI3K, but defective Pten inactivation ► Cbl-b suppresses Pten ubiquitination by impeding the binding of Pten to Nedd4 ► Nedd4 deficiency abrogates hyper-T cell responses in Cbl-b−/− mice
Cbl-b, an E3 ubiquitin ligase, regulates T cell activation presumably via PI3K, but the molecular mechanism is not fully understood. Zhang and colleagues unveil a previously unappreciated role of Cbl-b in T cell activation that is independent of its ubiquitin ligase activity. Cbl-b impedes the binding of Pten to another ubiquitin ligase, called Nedd4, which targets Pten for nonproteolytic modification, thus impairing Pten inactivation. Therefore, these data provide new insight into the regulation of T cell activation by Cbl-b.
Details
- Title: Subtitle
- E3 Ubiquitin Ligase Cbl-b Regulates Pten via Nedd4 in T Cells Independently of Its Ubiquitin Ligase Activity
- Creators
- Hui Guo - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USAGuilin Qiao - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USAHaiyan Ying - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USAZhenping Li - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USAYixia Zhao - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USAYanran Liang - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USALifen Yang - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USAStanley Lipkowitz - Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAJosef M Penninger - Institute of Molecular Biotechnology, The Austrian Academy of Sciences, 1030 Vienna, AustriaWallace Y Langdon - School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, AustraliaJian Zhang - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.1(5), pp.472-482
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2012.04.008
- PMID
- 22763434
- PMCID
- PMC3387815
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Language
- English
- Date published
- 05/31/2012
- Academic Unit
- Pathology
- Record Identifier
- 9984047692502771
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