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

Soo Mi Ki, Ji Hyun Kim, So Yeon Won, Shin Ji Oh, In Young Lee, Young Ki Bae, Ki Wha Chung, Byung Ok Choi, Boyoun Park, Eui Ju Choi, Ji Eun Lee

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere48290
JournalEMBO Reports
Volume21
Issue number2
DOIs
Publication statusPublished - 2020 Feb 5

Keywords

  • AURKA
  • CEP41
  • angiogenesis
  • primary cilia
  • tubulin glutamylation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Ki, S. M., Kim, J. H., Won, S. Y., Oh, S. J., Lee, I. Y., Bae, Y. K., Chung, K. W., Choi, B. O., Park, B., Choi, E. J., & Lee, J. E. (2020). CEP41-mediated ciliary tubulin glutamylation drives angiogenesis through AURKA-dependent deciliation. EMBO Reports, 21(2), [e48290]. https://doi.org/10.15252/embr.201948290