Dephosphorylation of Carma1 by PP2A negatively regulates T-cell activation.

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.
Mesh Terms:
Animals, CARD Signaling Adaptor Proteins, CD4-Positive T-Lymphocytes, DNA Primers, Electrophoretic Mobility Shift Assay, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Knockdown Techniques, Guanylate Cyclase, HEK293 Cells, Humans, Immunoprecipitation, Jurkat Cells, Luciferases, Lymphocyte Activation, Mice, Mice, Transgenic, Multiprotein Complexes, NF-kappa B, Phosphorylation, Protein Phosphatase 2, Reverse Transcriptase Polymerase Chain Reaction, Transduction, Genetic
EMBO J.
Date: Feb. 02, 2011
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