Muscolini Michela, Camperio Cristina, Porciello Nicla, Caristi Silvana, Capuano Cristina, Viola Antonella, Galandrini Ricciarda, Tuosto Loretta
Department of Biology and Biotechnology "Charles Darwin," Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University, 00185 Rome, Italy;
Department of Experimental Medicine, Sapienza University, 00185 Rome, Italy;
J Immunol. 2015 Feb 1;194(3):1323-33. doi: 10.4049/jimmunol.1401643. Epub 2014 Dec 24.
Phosphatidylinositol 4,5-biphosphate (PIP2) is a cell membrane phosphoinositide crucial for cell signaling and activation. Indeed, PIP2 is a pivotal source for second messenger generation and controlling the activity of several proteins regulating cytoskeleton reorganization. Despite its critical role in T cell activation, the molecular mechanisms regulating PIP2 turnover remain largely unknown. In human primary CD4(+) T lymphocytes, we have recently demonstrated that CD28 costimulatory receptor is crucial for regulating PIP2 turnover by allowing the recruitment and activation of the lipid kinase phosphatidylinositol 4-phosphate 5-kinase (PIP5Kα). We also identified PIP5Kα as a key modulator of CD28 costimulatory signals leading to the efficient T cell activation. In this study, we extend these data by demonstrating that PIP5Kα recruitment and activation is essential for CD28-mediated cytoskeleton rearrangement necessary for organizing a complete signaling compartment leading to downstream signaling functions. We also identified Vav1 as the linker molecule that couples the C-terminal proline-rich motif of CD28 to the recruitment and activation of PIP5Kα, which in turn cooperates with Vav1 in regulating actin polymerization and CD28 signaling functions.
磷脂酰肌醇4,5-二磷酸（PIP2）是一种细胞膜磷酸肌醇，对细胞信号传导和激活至关重要。事实上，PIP2是第二信使生成的关键来源，并控制着几种调节细胞骨架重组的蛋白质的活性。尽管其在T细胞激活中起着关键作用，但调节PIP2周转的分子机制仍 largely未知。在人类原代CD4(+) T淋巴细胞中，我们最近证明，CD28共刺激受体通过允许脂质激酶磷脂酰肌醇4-磷酸5-激酶（PIP5Kα）的募集和激活来调节PIP2周转至关重要。我们还确定PIP5Kα是导致有效T细胞激活的CD28共刺激信号的关键调节剂。在本研究中，我们通过证明PIP5Kα的募集和激活对于CD28介导的细胞骨架重排至关重要，而细胞骨架重排是组织完整信号区室以实现下游信号功能所必需的，从而扩展了这些数据。我们还确定Vav1是将CD28富含脯氨酸的C末端基序与PIP5Kα的募集和激活相偶联的接头分子，而PIP5Kα又与Vav1协同调节肌动蛋白聚合和CD28信号功能。
