T cell receptor signals to NF-κB are transmitted by a cytosolic p62-Bcl10-Malt1-IKK signalosome.
T cell receptor signals to NF-κB are transmitted by a cytosolic p62-Bcl10-Malt1-IKK signalosome.
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DOI：
10.1126/scisignal.2004882
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发表时间：
2014-05-13
影响因子：
7.3
通讯作者：
Schaefer BC
中科院分区：
文献类型：
--
作者：
Paul S;Traver MK;Kashyap AK;Washington MA;Latoche JR;Schaefer BC
抗原介导的T细胞受体（TCR）刺激触发核因子κB（NF-κB）的活化，核因子κ B是T细胞增殖和效应细胞分化的关键转录调节因子。TCR信号传导至NF-κB需要Carma 1-Bcl 10-Malt 1（CBM）复合物和κB（IκB）激酶抑制剂（IKK）复合物;然而，将CBM复合物与IKK激活联系起来的分子机制尚未完全确定。在这里，我们发现，活性IKK复合物是TCR依赖的细胞溶质Bcl 10-Malt 1信号体的一个组成部分，含有衔接蛋白p62，在效应T细胞中形成。磷酸化的IκBα和NF-κB在NF-κB转位到细胞核之前被瞬时募集到该信号体。抑制激酶TAK 1或IKK的活性可以阻断IKK的磷酸化，但不能阻断p62-Bcl 10-Malt 1簇的形成，这表明IKK的激活发生在信号体组装之后。此外，对来自p62缺陷小鼠的T细胞的分析表明，信号传导组分的p62依赖性聚集刺激了效应T细胞中NF-κB的活化。因此，TCR刺激的NF-κB活化需要胞质p62-Bcl 10-Malt 1-IKK信号体的组装，这可能确保响应于TCR接合的NF-κB的高度调节的活化。
Antigen-mediated stimulation of the T cell receptor (TCR) triggers activation of nuclear factor κB (NF-κB), a key transcriptional regulator of T cell proliferation and effector cell differentiation. TCR signaling to NF-κB requires both the Carma1-Bcl10-Malt1 (CBM) complex and the inhibitor of κB (IκB) kinase (IKK) complex; however, the molecular mechanisms connecting the CBM complex to activation of IKK are incompletely defined. Here, we found that the active IKK complex is a component of a TCR-dependent cytosolic Bcl10-Malt1 signalosome containing the adaptor protein p62, which forms in effector T cells. Phosphorylated IκBα and NF-κB were transiently recruited to this signalosome before NF-κB translocated to the nucleus. Inhibiting the activity of the kinases TAK1 or IKK blocked the phosphorylation of IKK, but not the formation of p62-Bcl10-Malt1 clusters, suggesting that activation of IKK occurs after signalosome assembly. Furthermore, analysis of T cells from p62-deficient mice demonstrated that the p62-dependent clustering of signaling components stimulated activation of NF-κB in effector T cells. Thus, TCR-stimulated activation of NF-κB requires the assembly of cytosolic p62-Bcl10-Malt1-IKK signalosomes, which may ensure highly regulated activation of NF-κB in response to TCR engagement.
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