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Open Access Green as soon as Postprint is submitted to ZB.
The Ca²⁺-dependent phosphatase calcineurin controls the formation of the Carma1-Bcl10-Malt1 complex during T cell receptor-induced NF-κB activation.
J. Biol. Chem. 286, 7522-7534 (2011)
T cell receptor (TCR) ligation induces increased diacylglycerol and Ca(2+) levels in T cells, and both secondary messengers are crucial for TCR-induced nuclear factor of activated T cells (NF-AT) and NF-κB signaling pathways. One prominent calcium-dependent enzyme involved in the regulation of NF-AT and NF-κB signaling pathways is the protein phosphatase calcineurin. However, in contrast to NF-AT, which is directly dephosphorylated by calcineurin, the molecular basis of the calcium-calcineurin dependence of the TCR-induced NF-κB activity remains largely unknown. Here, we demonstrate that calcineurin regulates TCR-induced NF-κB activity by controlling the formation of a protein complex composed of Carma1, Bcl10, and Malt1 (CBM complex). For instance, increased calcium levels induced by ionomycin or thapsigargin augmented the phorbol 12-myristate 13-acetate-induced formation of the CBM complex and activation of NF-κB, whereas removal of calcium by the calcium chelator EGTA-acetoxymethyl ester (AM) attenuated both processes. Furthermore, inhibition of the calcium-dependent phosphatase calcineurin with the immunosuppressive agent cyclosporin A (CsA) or FK506 as well as siRNA-mediated knockdown of calcineurin A strongly affected the PMA + ionomycin- or anti-CD3 + CD28-induced CBM complex assembly. Mechanistically, the positive effect of calcineurin on the CBM complex formation seems to be linked to a dephosphorylation of Bcl10. For instance, Bcl10 was found to be hyperphosphorylated in Jurkat T cells upon treatment with CsA or EGTA-AM, and calcineurin dephosphorylated Bcl10 in vivo and in vitro. Furthermore, we show here that calcineurin A interacts with the CBM complex. In summary, the evidence provided here argues for a previously unanticipated role of calcineurin in CBM complex formation as a molecular basis of the inhibitory function of CsA or FK506 on TCR-induced NF-κB activity.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Protein-kinase-C; PKC-Theta; Phosohorylation; Carma1; Lymphocytes; BCL10; Ubiquitination; Degradation; Interferes; Calmodulin
ISSN (print) / ISBN
0021-9258
e-ISSN
1083-351X
Quellenangaben
Volume: 286,
Issue: 9,
Pages: 7522-7534
Publisher
American Society for Biochemistry and Molecular Biology
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Signaling and Translation (SAT)