CEP41-mediated ciliary tubulin glutamylation drives angiogenesis through AURKA-dependent deciliation
CEP41-mediated ciliary tubulin glutamylation drives angiogenesis through AURKA-dependent deciliation
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DOI：
10.15252/embr.201948290
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发表时间：
2019-12-29
期刊：
影响因子：
7.7
通讯作者：
Lee, Ji Eun
中科院分区：
文献类型：
--
作者：
Ki, Soo Mi;Kim, Ji Hyun;Lee, Ji Eun
内皮纤毛是微管为基础的细胞器，在血管生成过程中负责血流诱导的机械感觉和信号转导。然而，纤毛机械感觉发生的确切功能和机制却知之甚少。尽管细胞质微管蛋白的翻译后修饰(PTM)在血管生成中具有重要作用，但睫状微管蛋白PTM的具体作用尚不清楚。在这里，我们报告了中心体蛋白41(CEP41)的缺失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。我们发现，CEP41对微管蛋白谷氨酰化的适当控制是纤毛分解所必需的，它参与了内皮细胞(EC)的迁移和微管形成等动力学过程。我们发现，在对剪切力或缺氧做出反应的内皮细胞中，CEP41激活极光激酶A(AURKA)，通过纤毛微管蛋白谷氨化上调VEGFA和VEGFR2的表达，并导致其降解。我们进一步证明，在低氧诱导的血管生成中，CEP41负责激活HIF1α，从而触发AURKA-VEGF途径。总之，我们的结果表明CEP41-HIF1α-AURKA-VEGF轴是血管生成的关键分子机制，并证明了睫状小管蛋白谷氨化在机械感觉反应的EC动力学中是多么重要。
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 HIF1 alpha to trigger the AURKA-VEGF pathway. Overall, our results suggest the CEP41-HIF1 alpha-AURKA-VEGF axis as a key molecular mechanism of angiogenesis and demonstrate how important ciliary tubulin glutamylation is in mechanosense-responded EC dynamics.