Interaction of calmodulin with Bcl10 modulates NF-kappaB activation.
Calcium signals resulting from antigen receptor activation are important in determining the responses of a T or B lymphocyte to an antigen. Calmodulin (CaM), a multi-functional sensor of intracellular calcium (Ca(2+)) signals in cells, is required in the pathway from the T cell receptor (TCR) to activation of the key transcription factor NF-kappaB. Here we searched for a partner in direct interaction with CaM in the pathway, and found that CaM interacts specifically with the signaling adaptor Bcl10. The binding is Ca(2+) dependent and of high affinity, with a K(d) of approximately 160 nM. Proximity of CaM and Bcl10 in vivo is induced by increases in the intracellular Ca(2+) level. The interaction is localized to the CARD domain of Bcl10, which interacts with the CARD domain of the upstream signaling partner Carma1. Binding of CaM to Bcl10 is shown to inhibit the ability of Bcl10 to interact with Carma1, an interaction that is required for signaling from the TCR to NF-kappaB. Furthermore, a mutant of Bcl10 with reduced binding to CaM shows increased activation of an NF-kappaB reporter, which is further enhanced by activating stimuli. We propose a novel mechanism whereby the Ca(2+) sensor CaM regulates T cell responses to antigens by binding to Bcl10, thereby modulating its interaction with Carma1 and subsequent activation of NF-kappaB.
Edin
Sofia
S
Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
Oruganti
Sreenivasa Rao
SR
Grundström
Christine
C
Grundström
Thomas
T
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000595:Amino Acid Sequence; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001665:Binding Sites; D053468:CARD Signaling Adaptor Proteins / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D002147:Calmodulin / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D002147:Calmodulin; D016328:NF-kappa B; D009363:Neoplasm Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase