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.
N1 - © 2018 Kovačević et al.
PY - 2018/3/5
Y1 - 2018/3/5
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 RhoB-mediated 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 RhoB-mediated EC contraction
KW - Carrier Proteins/genetics
KW - Cullin Proteins/genetics
KW - Human Umbilical Vein Endothelial Cells/cytology
KW - Humans
KW - Potassium Channels, Voltage-Gated/genetics
KW - Ubiquitination
KW - rhoB GTP-Binding Protein/genetics
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85042848727&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29358211
U2 - https://doi.org/10.1083/jcb.201606055
DO - https://doi.org/10.1083/jcb.201606055
M3 - Article
C2 - 29358211
SN - 0021-9525
VL - 217
SP - 1015
EP - 1032
JO - Journal of cell biology
JF - Journal of cell biology
IS - 3
ER -