Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
Mol Immunol. 2010 Jul;47(11-12):2057-64. doi: 10.1016/j.molimm.2010.04.005. Epub 2010 May 1.
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.
抗原受体激活引起的钙信号在决定 T 或 B 淋巴细胞对抗原的反应中非常重要。钙调蛋白（CaM）是细胞内钙（Ca(2+)）信号的多功能传感器，在 T 细胞受体（TCR）到关键转录因子 NF-κB 激活的途径中是必需的。在这里，我们在该途径中搜索与 CaM 直接相互作用的伴侣，发现 CaM 特异性地与信号适配器 Bcl10 相互作用。结合是 Ca(2+)依赖的，具有高亲和力，K(d)约为 160 nM。细胞内 Ca(2+)水平升高诱导 CaM 和 Bcl10 在体内的接近。这种相互作用定位于 Bcl10 的 CARD 结构域，该结构域与上游信号伴侣 Carma1 的 CARD 结构域相互作用。CaM 与 Bcl10 的结合被证明抑制了 Bcl10 与 Carma1 相互作用的能力，而这种相互作用是 TCR 到 NF-κB 信号所必需的。此外，与 CaM 结合减少的 Bcl10 突变体显示出 NF-κB 报告基因的激活增加，而激活刺激进一步增强了这种激活。我们提出了一种新的机制，即 Ca(2+)传感器 CaM 通过与 Bcl10 结合来调节 T 细胞对抗原的反应，从而调节其与 Carma1 的相互作用以及随后 NF-κB 的激活。
