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.
Bibliographical noteFunding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant (2017R1E1A2A01076144 and 2018R1A2A3074597 to J.E.L. and 2018R1A4A1024506 to K.W.C., B.‐O.C., and J.E.L.) and the BRL grant (NRF 2015041919 to E.‐J.C.) funded by the Korean government (MSIP). We thank J.‐S. Lee (KRIBB) for Tg(kdrl:eGFP) zebrafish; J.‐H. Kim and D.‐H. Jo (Seoul National University) for advices on angiogenesis analysis; S.‐K. Choe (Wonkwang University) for pT7‐gRNA vector; H.‐S. Park (University of Seoul) for human HIF1α DNA; and H.W.Ko (Dongguk University) for comments on the manuscript.
All Science Journal Classification (ASJC) codes
- Molecular Biology