| First Author | Eitelhuber AC | Year | 2011 |
| Journal | EMBO J | Volume | 30 |
| Issue | 3 | Pages | 594-605 |
| PubMed ID | 21157432 | Mgi Jnum | J:169250 |
| Mgi Id | MGI:4940154 | Doi | 10.1038/emboj.2010.331 |
| Citation | Eitelhuber AC, et al. (2011) Dephosphorylation of Carma1 by PP2A negatively regulates T-cell activation. EMBO J 30(3):594-605 |
| abstractText | The Carma1-Bcl10-Malt1 (CBM) complex bridges T-cell receptor (TCR) signalling to the canonical IkappaB kinase (IKK)/NF-kappaB pathway. NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-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 Aalpha (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 PKCtheta-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-kappaB activation and IL-2 or IFN-gamma 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. |
