The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB

Igor Kovačević, Tomohisa Sakaue, Jisca Majoleé, Manon C. Pronk, Masashi Maekawa, Dirk Geerts, Mar Fernandez-Borja, Shigeki Higashiyama, Peter L. Hordijk

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

RhoGTPases control endothelial cell (EC) migration, adhesion, and barrier formation. Whereas the relevance of RhoA for endothelial barrier function is widely accepted, the role of the RhoA homologue RhoB is poorly defined. RhoB and RhoA are 85% identical, but RhoB's subcellular localization and half-life are uniquely different. Here, we studied the role of ubiquitination for the function and stability of RhoB in primary human ECs. We show that the K63 polyubiquitination at lysine 162 and 181 of RhoB targets the protein to lysosomes. Moreover, we identified the RING E3 ligase complex Cullin-3-Rbx1-KCTD10 as key modulator of endothelial barrier integrity via its regulation of the ubiquitination, localization, and activity of RhoB. In conclusion, our data show that ubiquitination controls the subcellular localization and lysosomal degradation of RhoB and thereby regulates the stability of the endothelial barrier through control of RhoBmediated EC contraction.
Original languageEnglish
Pages (from-to)1015-1032
JournalJournal of Cell Biology
Volume217
Issue number3
DOIs
Publication statusPublished - 2018

Cite this

Kovačević, Igor ; Sakaue, Tomohisa ; Majoleé, Jisca ; Pronk, Manon C. ; Maekawa, Masashi ; Geerts, Dirk ; Fernandez-Borja, Mar ; Higashiyama, Shigeki ; Hordijk, Peter L. / The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB. In: Journal of Cell Biology. 2018 ; Vol. 217, No. 3. pp. 1015-1032.
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title = "The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB",
abstract = "RhoGTPases control endothelial cell (EC) migration, adhesion, and barrier formation. Whereas the relevance of RhoA for endothelial barrier function is widely accepted, the role of the RhoA homologue RhoB is poorly defined. RhoB and RhoA are 85{\%} identical, but RhoB's subcellular localization and half-life are uniquely different. Here, we studied the role of ubiquitination for the function and stability of RhoB in primary human ECs. We show that the K63 polyubiquitination at lysine 162 and 181 of RhoB targets the protein to lysosomes. Moreover, we identified the RING E3 ligase complex Cullin-3-Rbx1-KCTD10 as key modulator of endothelial barrier integrity via its regulation of the ubiquitination, localization, and activity of RhoB. In conclusion, our data show that ubiquitination controls the subcellular localization and lysosomal degradation of RhoB and thereby regulates the stability of the endothelial barrier through control of RhoBmediated EC contraction.",
author = "Igor Kovačević and Tomohisa Sakaue and Jisca Majole{\'e} and Pronk, {Manon C.} and Masashi Maekawa and Dirk Geerts and Mar Fernandez-Borja and Shigeki Higashiyama and Hordijk, {Peter L.}",
year = "2018",
doi = "10.1083/jcb.201606055",
language = "English",
volume = "217",
pages = "1015--1032",
journal = "Journal of Cell Biology",
issn = "0021-9525",
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Kovačević, I, Sakaue, T, Majoleé, J, Pronk, MC, Maekawa, M, Geerts, D, Fernandez-Borja, M, Higashiyama, S & Hordijk, PL 2018, 'The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB' Journal of Cell Biology, vol. 217, no. 3, pp. 1015-1032. https://doi.org/10.1083/jcb.201606055

The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB. / Kovačević, Igor; Sakaue, Tomohisa; Majoleé, Jisca; Pronk, Manon C.; Maekawa, Masashi; Geerts, Dirk; Fernandez-Borja, Mar; Higashiyama, Shigeki; Hordijk, Peter L.

In: Journal of Cell Biology, Vol. 217, No. 3, 2018, p. 1015-1032.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB

AU - Kovačević, Igor

AU - Sakaue, Tomohisa

AU - Majoleé, Jisca

AU - Pronk, Manon C.

AU - Maekawa, Masashi

AU - Geerts, Dirk

AU - Fernandez-Borja, Mar

AU - Higashiyama, Shigeki

AU - Hordijk, Peter L.

PY - 2018

Y1 - 2018

N2 - RhoGTPases control endothelial cell (EC) migration, adhesion, and barrier formation. Whereas the relevance of RhoA for endothelial barrier function is widely accepted, the role of the RhoA homologue RhoB is poorly defined. RhoB and RhoA are 85% identical, but RhoB's subcellular localization and half-life are uniquely different. Here, we studied the role of ubiquitination for the function and stability of RhoB in primary human ECs. We show that the K63 polyubiquitination at lysine 162 and 181 of RhoB targets the protein to lysosomes. Moreover, we identified the RING E3 ligase complex Cullin-3-Rbx1-KCTD10 as key modulator of endothelial barrier integrity via its regulation of the ubiquitination, localization, and activity of RhoB. In conclusion, our data show that ubiquitination controls the subcellular localization and lysosomal degradation of RhoB and thereby regulates the stability of the endothelial barrier through control of RhoBmediated EC contraction.

AB - RhoGTPases control endothelial cell (EC) migration, adhesion, and barrier formation. Whereas the relevance of RhoA for endothelial barrier function is widely accepted, the role of the RhoA homologue RhoB is poorly defined. RhoB and RhoA are 85% identical, but RhoB's subcellular localization and half-life are uniquely different. Here, we studied the role of ubiquitination for the function and stability of RhoB in primary human ECs. We show that the K63 polyubiquitination at lysine 162 and 181 of RhoB targets the protein to lysosomes. Moreover, we identified the RING E3 ligase complex Cullin-3-Rbx1-KCTD10 as key modulator of endothelial barrier integrity via its regulation of the ubiquitination, localization, and activity of RhoB. In conclusion, our data show that ubiquitination controls the subcellular localization and lysosomal degradation of RhoB and thereby regulates the stability of the endothelial barrier through control of RhoBmediated EC contraction.

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SN - 0021-9525

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