CEP41‐mediated ciliary tubulin glutamylation drives angiogenesis through AURKA‐dependent deciliation

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. Synopsis CEP41 regulates cilia disassembly and angiogenesis through AURKA activation by modulating axonemal tubulin glutamylation in mammalian and zebrafish endothelial cells. CEP41‐mediated axonemal tubulin glutamylation is essential for endothelial cell dynamics during angiogenesis. CEP41 activates AURKA and upregulates VEGFA/VEGFR2 mRNAs to promote endothelia cellular deciliation under shear stress. CEP41 interacts with HIF1α and inhibits its UPS‐dependent degradation under hypoxia. CEP41 controls HIF1α activation to trigger AURKA‐VEGF pathway in hypoxia‐induced angiogenesis. Graphical Abstract CEP41 regulates cilia disassembly and angiogenesis through AURKA activation by modulating axonemal tubulin glutamylation in mammalian and zebrafish endothelial cells.