title: CaMKII targets Bcl10 in T-cell receptor induced activation of NF-κB.
abstract: Recognition of antigen by T- or B-cell receptors leads to formation of an immunological synapse and initiation of signalling events that collaborate to determine the nature of the adaptive immune response. Activation of NF-κB transcription factors has a key role in regulation of numerous genes with important functions in immune responses and inflammation and is of great importance for lymphocyte activation and differentiation. The activation of NF-κB depends on changes in intracellular Ca(2+) levels, and both calmodulin (CaM) and a CaM-dependent kinase, CaMKII, help regulate NF-κB activation after T-cell receptor (TCR) stimulation, but the mechanisms are not well characterized. Here we have analyzed the functional role of CaMKII in the signalling pathway from the TCR to activation of IKK, the kinase that phosphorylates the NF-κB inhibitor IκB. We show that CaMKII is recruited to the immunological synapse where it interacts with and phosphorylates the signalling adaptor protein Bcl10. Furthermore, phosphorylation of the CARD domain of Bcl10 by CaMKII regulates the interactions within the important Carma1, Bcl10, Malt1 signalling complex and the essential signal induced ubiquitinations of Bcl10 and IKKγ. We propose a novel mechanism whereby Ca(2+) signals can be integrated at the immunological synapse through CaMKII-dependent phosphorylation of Bcl10.
authors.affiliation: Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Sreenivasa Rao
authors.initials: SR
authors.lastname: Oruganti
authors.forename: Sofia
authors.initials: S
authors.lastname: Edin
authors.forename: Christine
authors.initials: C
authors.lastname: Grundström
authors.forename: Thomas
authors.initials: T
authors.lastname: Grundström
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D054992:Immunological Synapses / Q000378:metabolism*; D019169:Jurkat Cells; D018613:Microscopy, Confocal; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016415:Sequence Alignment; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D051550:I-kappa B Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium