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

Abstract

CARMA1 is a central regulator of NF-κB activation in lymphocytes. CARMA1 and Bcl10 functionally interact and control NF-κB 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-κB activation induced by TCR stimulation. Furthermore, CaMKII enhances CARMA1-induced NF-κB 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-κB activation.

Supplemental material for this article may be found at http://mcb.asm.org/.

This work was supported by grants from CCFA, DK43351, and Career Development Funds to R.J.X., and K.I. was supported by the Fellowship of Uehara Memorial Foundation.

We thank Brian Seed, Joe Avruch, Adrian Ting, John Rioux, and Ian Rosenberg for discussions and/or review of the manuscript. We thank Xin Lin, Dan Billadeau, Michael Karin, Richard Maurer, Adrian Ting, and Jürg Tschopp for generous provision of research materials.

We declare that we have no competing financial interests.