| Autor: |
Eitelhuber AC; Department of Cellular Signal Integration, Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Toxicology, Neuherberg, Germany., Warth S, Schimmack G, Düwel M, Hadian K, Demski K, Beisker W, Shinohara H, Kurosaki T, Heissmeyer V, Krappmann D |
| Jazyk: |
angličtina |
| Zdroj: |
The EMBO journal [EMBO J] 2011 Feb 02; Vol. 30 (3), pp. 594-605. Date of Electronic Publication: 2010 Dec 14. |
| DOI: |
10.1038/emboj.2010.331 |
| Abstrakt: |
The Carma1-Bcl10-Malt1 (CBM) complex bridges T-cell receptor (TCR) signalling to the canonical IκB kinase (IKK)/NF-κB pathway. NF-κB activation is triggered by PKCθ-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCθ-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane. We have identified the serine-threonine protein phosphatase PP2A regulatory subunit Aα (PPP2R1A) as a novel interaction partner of Carma1. PPP2R1A is associated with Carma1 in resting as well as activated T cells in the context of the active CBM complex. By siRNA-mediated knockdown and in vitro dephosphorylation, we demonstrate that PP2A removes PKCθ-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. As a result of PP2A inactivation, we find that enhanced Carma1 S645 phosphorylation augments CBM complex formation, NF-κB activation and IL-2 or IFN-γ production after stimulation of Jurkat T cells or murine Th1 cells. Thus, our data define PP2A-mediated dephosphorylation of Carma1 as a critical step to limit T-cell activation and effector cytokine production. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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