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

doi:10.15252/embr.201948290

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

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17 Citations (Scopus)

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 language	English
Article number	e48290
Journal	EMBO Reports
Volume	21
Issue number	2
DOIs	https://doi.org/10.15252/embr.201948290
Publication status	Published - 2020 Feb 5

Bibliographical note

Funding 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.

Funding 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 HIF1? DNA; and H.W.Ko (Dongguk University) for comments on the manuscript.

Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology
Genetics

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10.15252/embr.201948290

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@article{022a63d3d756467d9b0b68119c61d2dc,

title = "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 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.",

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

note = "Funding 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. Funding 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 HIF1? DNA; and H.W.Ko (Dongguk University) for comments on the manuscript. Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2020",

month = feb,

day = "5",

doi = "10.15252/embr.201948290",

language = "English",

volume = "21",

journal = "EMBO Reports",

issn = "1469-221X",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - CEP41-mediated ciliary tubulin glutamylation drives angiogenesis through AURKA-dependent deciliation

AU - Ki, Soo Mi

AU - Kim, Ji Hyun

AU - Won, So Yeon

AU - Oh, Shin Ji

AU - Lee, In Young

AU - Bae, Young Ki

AU - Chung, Ki Wha

AU - Choi, Byung Ok

AU - Park, Boyoun

AU - Choi, Eui Ju

AU - Lee, Ji Eun

N1 - Funding 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. Funding 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 HIF1? DNA; and H.W.Ko (Dongguk University) for comments on the manuscript. Publisher Copyright: © 2019 The Authors. Published under the terms of the CC BY 4.0 license

PY - 2020/2/5

Y1 - 2020/2/5

N2 - 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.

AB - 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.

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DO - 10.15252/embr.201948290

M3 - Article

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SN - 1469-221X

VL - 21

JO - EMBO Reports

JF - EMBO Reports

IS - 2

M1 - e48290

ER -

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

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