Abstract A087: Phase separation of signaling molecules promotes T cell receptor signal transduction
Abstract A087: Phase separation of signaling molecules promotes T cell receptor signal transduction
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摘要 A087：信号分子的相分离促进 T 细胞受体信号转导
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发表时间：
2016
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通讯作者：
R. Vale
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作者：
Xiaolei Su;J. Ditlev;E. Hui;Sudeep Banjade;Julia Okrut;J. Taunton;M. Rosen;R. Vale
信号通过T细胞受体（TCR）介导T细胞活化、分化和增殖。先前的显微镜研究表明，TCR激活后，信号分子在质膜上的空间重组成微团簇。然而，微团簇是如何形成的以及这些结构在信号转导中起什么作用仍不清楚。重要的是，缺乏对聚集状态和非聚集状态下信号分子的生化活性的直接比较。在这里，我们通过用12种纯化蛋白在体外重建TCR信号通路来解决这些问题，从TCR磷酸化开始，最终在肌动蛋白聚合中结束。我们表明，在磷酸化启动后，多价蛋白-蛋白相互作用驱动信号分子的相分离成显示液体样特性的微团簇。这些团簇富集激酶，但排除磷酸酶，从而维持蛋白质磷酸化。我们还直接证明了肌动蛋白调节蛋白重组成这些簇，大大增强了肌动蛋白丝在膜上的组装。这些结果表明，微团簇创造了独特的物理和生化环境，促进了TCR信号的反应。这里揭示的原理可能适用于其他利用相分离来调节膜、细胞质或细胞核上的生化反应的系统。引文格式：苏晓雷，Jon Ditlev, Hui Enfu, Sudeep Banjade, Julia Okrut, Jack Taunton, Mike Rosen, Ron Vale。信号分子相分离促进T细胞受体信号转导。[摘要]。CRI-CIMT-EATI-AACR首届国际癌症免疫治疗会议论文集：将科学转化为生存；2015年9月16日至19日；纽约，纽约。费城（PA）： AACR；Cancer Immunol Res 2016；4（1增刊）：摘要nr A087。
Signaling through the T cell receptor (TCR) mediates T cell activation, differentiation, and proliferation. Previous microscopy studies have shown the spatial reorganization of signaling molecules into microclusters on the plasma membrane after TCR activation. However, how microclusters form and what roles these structures play in signal transduction remain unclear. Importantly, direct comparison of the biochemical activities of signaling molecules in the clustered versus unclustered state has been lacking. Here, we address these questions by reconstituting a TCR signaling pathway in vitro with 12 purified proteins, beginning with TCR phosphorylation and culminating in actin polymerization. We show that upon initiation of phosphorylation, multivalent protein-protein interactions drive the phase separation of signaling molecules into microclusters that display liquid-like properties. These clusters enrich kinases but exclude phosphatases, thus sustaining protein phosphorylation. We also directly demonstrate that the reorganization of actin regulatory proteins into these clusters substantially enhances actin filament assembly at the membrane. These results establish that microclusters create unique physical and biochemical environments that promote reactions in TCR signaling. The principles revealed here likely apply to other systems that exploit phase separation to regulate biochemical reactions on membranes, in the cytoplasm, or the nucleus. Citation Format: Xiaolei Su, Jon Ditlev, Enfu Hui, Sudeep Banjade, Julia Okrut, Jack Taunton, Mike Rosen, Ron Vale. Phase separation of signaling molecules promotes T cell receptor signal transduction. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A087.