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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • CUL3 protein, human
  • Carrier Proteins
  • Cullin Proteins
  • KCTD10 protein, human
  • Potassium Channels, Voltage-Gated
  • RBX1 protein, human
  • rhoB GTP-Binding Protein

Associated data

  • PDB/2FV8