CEP41‐mediated ciliary tubulin glutamylation drives angiogenesis through AURKA‐dependent deciliation
Open Access
- 29 December 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Reports
- Vol. 21 (2), e48290
- https://doi.org/10.15252/embr.201948290
Abstract
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.Keywords
Funding Information
- National Research Foundation of Korea (2017R1E1A2A01076144, 2018R1A2A3074597, 2018R1A4A1024506, NRF 2015041919)
This publication has 56 references indexed in Scilit:
- HIF inhibitors for ischemic retinopathies and cancers: options beyond anti-VEGF therapiesAngiogenesis, 2016
- Dynamic Endothelial Cell Rearrangements Drive Developmental Vessel RegressionPLoS Biology, 2015
- Rac1 and Aurora A regulate MCAK to polarize microtubule growth in migrating endothelial cellsThe Journal of cell biology, 2014
- Dynamic responses of endothelial cells to changes in blood flow during vascular remodeling of the mouse yolk sacDevelopment, 2013
- Role of the Cytoskeleton in Formation and Maintenance of Angiogenic SproutsJournal of Vascular Research, 2011
- Distinct ECM mechanosensing pathways regulate microtubule dynamics to control endothelial cell branching morphogenesisThe Journal of cell biology, 2011
- The Golgi and the centrosome: building a functional partnershipThe Journal of cell biology, 2010
- Organelle positioning and cell polarityNature Reviews Molecular Cell Biology, 2008
- Endothelial Cell Migration During AngiogenesisCirculation Research, 2007
- Angiogenesis in life, disease and medicineNature, 2005