Phase separation of signaling molecules promotes T cell receptor signal transduction.
Phase separation of signaling molecules promotes T cell receptor signal transduction.
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DOI：
10.1126/science.aad9964
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发表时间：
2016-04-29
期刊：
影响因子：
--
通讯作者：
Vale RD
中科院分区：
文献类型：
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作者：
Su X;Ditlev JA;Hui E;Xing W;Banjade S;Okrut J;King DS;Taunton J;Rosen MK;Vale RD
各种细胞表面受体的激活触发下游信号分子重组为微米或亚微米大小的簇。然而，这种聚类的功能后果尚不清楚。我们在模型膜上通过生化方法重建了一条由 12 部分组成的信号通路，从 T 细胞受体 (TCR) 激活开始，到肌动蛋白组装结束。当 TCR 磷酸化被触发时，下游信号蛋白自发分离成液体状簇，促进体外和人 Jurkat T 细胞中的信号输出。重建的簇富含激酶，但排除了磷酸酶，并通过招募和组织肌动蛋白调节剂来增强肌动蛋白丝组装。这些结果表明，蛋白质相分离可以创建独特的物理和生化区室，促进信号传导。 T 细胞信号通路的重建和相关细胞研究揭示了分子相分离成微团簇如何促进生化反应和信号反应。
Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micron- or submicron-sized clusters. However, the functional consequences of such clustering has been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phoshophorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases, and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling. Reconstitution of a T cell signaling pathway and correlative cellular studies reveal how phase separation of molecules into microclusters can promote biochemical reactions and signaling responses.