Format

Send to

Choose Destination
J Cell Biol. 2018 Mar 5;217(3):1015-1032. doi: 10.1083/jcb.201606055. Epub 2018 Jan 22.

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

Author information

1
Department of Molecular Cell Biology, Sanquin Research, Amsterdam, Netherlands.
2
Department of Physiology, Vrije Universiteit University Medical Center, Amsterdam, Netherlands.
3
Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Ehime, Japan.
4
Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
5
Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
6
Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
7
Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Ehime, Japan shigeki@m.ehime-u.ac.jp.
8
Department of Physiology, Vrije Universiteit University Medical Center, Amsterdam, Netherlands p.hordijk@vumc.nl.

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 RhoB-mediated EC contraction.

PMID:
29358211
PMCID:
PMC5839774
DOI:
10.1083/jcb.201606055
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center