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Ca²⁺/Calmodulin-Dependent Protein Kinase II Is a Modulator of CARMA1-Mediated NF-B Activation

Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114,¹ Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts 02114,² Department of Therapeutic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan 466-8550,³ The Broad Institute of Harvard and Massachusetts Institute of Technology and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114,⁴ Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114⁵

Received 26 December 2005/ Returned for modification 2 February 2006/ Accepted 8 April 2006

CARMA1 is a central regulator of NF-B activation in lymphocytes. CARMA1 and Bcl10 functionally interact and control NF-B signaling downstream of the T-cell receptor (TCR). Computational analysis of expression neighborhoods of CARMA1-Bcl10MALT 1 for enrichment in kinases identified calmodulin-dependent protein kinase II (CaMKII) as an important component of this pathway. Here we report that Ca²⁺/CaMKII is redistributed to the immune synapse following T-cell activation and that CaMKII is critical for NF-B activation induced by TCR stimulation. Furthermore, CaMKII enhances CARMA1-induced NF-B activation. Moreover, we have shown that CaMKII phosphorylates CARMA1 on Ser109 and that the phosphorylation facilitates the interaction between CARMA1 and Bcl10. These results provide a novel function for CaMKII in TCR signaling and CARMA1-induced NF-B activation.

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