RRC ID 50075
Author Kovačević I, Sakaue T, Majoleé J, Pronk MC, Maekawa M, Geerts D, Fernandez-Borja M, Higashiyama S, Hordijk PL.
Title The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB.
Journal J Cell Biol
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.
Volume 217(3)
Pages 1015-1032
Published 2018-3-5
DOI 10.1083/jcb.201606055
PII jcb.201606055
PMID 29358211
PMC PMC5839774
MeSH Carrier Proteins / genetics Carrier Proteins / metabolism* Cullin Proteins / genetics Cullin Proteins / metabolism* Human Umbilical Vein Endothelial Cells / cytology Human Umbilical Vein Endothelial Cells / metabolism* Humans Potassium Channels, Voltage-Gated / genetics Potassium Channels, Voltage-Gated / metabolism* Ubiquitination* rhoB GTP-Binding Protein / genetics rhoB GTP-Binding Protein / metabolism*
IF 8.811
Times Cited 13
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394).