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

ABSTRACT: The endothelial cilium is a microtubule-based organelle responsible for blood flow-induced mechanosensation during angiogenesis. The precise function and mechanisms by which ciliary mechanosensation occurs, however, are poorly understood. Although 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 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 EC dynamics. We show that in ECs responding to shear stress or hypoxia, CEP41 activates AURKA and up-regulates 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? to trigger the AURKA-VEGF pathway. Overall, our results suggest the CEP41-HIF1?-AURKA-VEGF axis as a key molecular mechanism of angiogenesis and demonstrate how important ciliary tubulin glutamylation is in mechanosense-responded EC dynamics.

SUBMITTER: Prof. Ji Eun Lee 

PROVIDER: S-SCDT-EMBOR-2019-48290V1 | biostudies-other |

REPOSITORIES: biostudies-other