The endothelial cilium is a microtubule-based organelle responsible for blood flow-induced mechanosensation and signal transduction during angiogenesis. The precise function and mechanisms by which ciliary mechanosensation occurs, however, are poorly understood. Although posttranslational modifications (PTMs) of cytoplasmic tubulin are known to be important in angiogenesis, the specific roles of ciliary tubulin PTMs play remain unclear. Here, we report that loss of centrosomal protein 41 (CEP41) results in vascular impairment in human cell lines and zebrafish, implying a previously unknown pro-angiogenic role for CEP41. We show that proper control of tubulin glutamylation by CEP41 is necessary for cilia disassembly and that is involved in endothelial cell (EC) dynamics such as migration and tubulogenesis. We show that in ECs responding to shear stress or hypoxia, CEP41 activates Aurora kinase A (AURKA) and upregulates expression of VEGFA and VEGFR2 through ciliary tubulin glutamylation, as well as leads to the deciliation. We further show that in hypoxia-induced angiogenesis, CEP41 is responsible for the activation of HIF1α to trigger the AURKA-VEGF pathway. Overall, our results suggest the CEP41-HIF1α-AURKA-VEGF axis as a key molecular mechanism of angiogenesis and demonstrate how important ciliary tubulin glutamylation is in mechanosense-responded EC dynamics.

中文翻译：

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CEP41 介导的纤毛微管蛋白谷氨酰化通过 AURKA 依赖性脱纤毛驱动血管生成。

内皮纤毛是一种基于微管的细胞器，负责血管生成过程中血流诱导的机械感觉和信号转导。然而，人们对纤毛机械感觉发生的精确功能和机制知之甚少。尽管已知细胞质微管蛋白的翻译后修饰 (PTM) 在血管生成中很重要，但睫状微管蛋白 PTM 的具体作用仍不清楚。在这里，我们报告中心体蛋白 41 (CEP41) 的丢失会导致人类细胞系和斑马鱼的血管损伤，这意味着 CEP41 具有以前未知的促血管生成作用。我们表明，CEP41 对微管蛋白谷氨酰化的适当控制对于纤毛解体是必要的，并且参与内皮细胞 (EC) 动力学，例如迁移和微管发生。我们发现，在响应剪切应力或缺氧的 EC 中，CEP41 激活极光激酶 A (AURKA)，并通过纤毛微管蛋白谷氨酰化上调 VEGFA 和 VEGFR2 的表达，并导致纤毛脱落。我们进一步表明，在缺氧诱导的血管生成中，CEP41 负责激活 HIF1α 以触发 AURKA-VEGF 通路。总的来说，我们的结果表明 CEP41-HIF1α-AURKA-VEGF 轴是血管生成的关键分子机制，并证明了睫状微管蛋白谷氨酰化在机械感应响应的 EC 动力学中的重要性。