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The Ca2+-dependent phosphatase calcineurin controls the formation of the Carma1-Bcl10-Malt1 complex during T cell receptor-induced NF-kappaB activation.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Mar 04; Vol. 286 (9), pp. 7522-34. Date of Electronic Publication: 2011 Jan 03. - Publication Year :
- 2011
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Abstract
- 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.
- Subjects :
- Adaptor Proteins, Signal Transducing immunology
Animals
B-Cell CLL-Lymphoma 10 Protein
CARD Signaling Adaptor Proteins immunology
Calcineurin genetics
Calcineurin immunology
Calcium metabolism
Caspases immunology
Cyclosporine pharmacology
Egtazic Acid analogs & derivatives
Egtazic Acid pharmacology
Guanylate Cyclase immunology
HEK293 Cells
Humans
Immunosuppressive Agents pharmacology
Jurkat Cells
Mice
Mice, Inbred Strains
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
NF-kappa B immunology
Neoplasm Proteins immunology
Phosphorylation immunology
RNA, Small Interfering
Signal Transduction immunology
T-Lymphocytes cytology
T-Lymphocytes drug effects
Tacrolimus pharmacology
Adaptor Proteins, Signal Transducing metabolism
CARD Signaling Adaptor Proteins metabolism
Calcineurin metabolism
Caspases metabolism
Guanylate Cyclase metabolism
NF-kappa B metabolism
Neoplasm Proteins metabolism
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21199863
- Full Text :
- https://doi.org/10.1074/jbc.M110.155895