Post-translational polymodification of ß 1 tubulin regulates motor protein localisation in platelet production and function
Post-translational polymodification of ß 1 tubulin regulates motor protein localisation in platelet production and function
复制标题
α1 微管蛋白的翻译后多修饰调节血小板生成和功能中的运动蛋白定位
DOI：
10.1101/595868
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Khan A
中科院分区：
文献类型：
--
作者：
Khan A
在特化细胞中，特定微管蛋白亚型的表达及其随后的翻译后修饰驱动和协调独特的形态和行为。B1-微管蛋白，即血小板和巨核细胞(MK)谱系限制微管蛋白亚型，驱动血小板产生和功能的机制仍然知之甚少。我们利用一组血小板减少患者、人类诱导多能干细胞来源的MK和健康的人类供者血小板，研究了两种关键的翻译后微管蛋白多聚修饰(聚谷氨酰化和聚甘氨酸化)在这些过程中的作用。我们在MK和血小板中发现了不同的多聚修饰模式，这是由细胞特异性表达的微管蛋白酪氨酸连接酶和胞浆羧肽酶的拮抗活性介导的。由此产生的微管图案化在空间上调节运动蛋白，以驱动巨核细胞中的原血小板形成，以及血栓形成所需的细胞骨架重组。这项工作是第一次展示了一个可逆的多聚修饰系统，通过它可以实现不同的细胞特定功能。
In specialized cells, the expression of specific tubulin isoforms and their subsequent post-translational modifications drive and coordinate unique morphologies and behaviors. The mechanisms by which b1-tubulin, the platelet and megakaryocyte (MK) lineage restricted tubulin isoform, drives platelet production and function remains poorly understood. We investigated the roles of two key post-translational tubulin polymodifications (polyglutamylation and polyglycylation) on these processes using a cohort of thrombocytopenic patients, human induced pluripotent stem cell derived MK, and healthy human donor platelets. We find distinct patterns of polymodification in MK and platelets, mediated by the antagonistic activities of the cell specific expression of tubulin tyrosine ligase like enzymes and cytosolic carboxypeptidase enzymes. The resulting microtubule patterning spatially regulates motor proteins to drive proplatelet formation in megakaryocytes, and the cytoskeletal reorganization required for thrombus formation. This work is the first to show a reversible system of polymodification by which different cell specific functions are achieved.