Figure 9.

Proposed schema of EC barrier regulation by ubiquitin carboxyl terminal hydrolase 1 (UCHL1). UCHL1 promotes VE-cadherin expression levels via inhibition of its deubiquitination and subsequent proteasomal degradation. In turn, VE-cadherin promotes claudin-5 expression by preventing the nuclear accumulation of β-catenin and FoxO1, transcriptional repressors of claudin-5. The combined effects of increased VE-cadherin and claudin-5 at the membrane augment EC barrier function. Conversely, decreased UCHL1 expression is associated with increased proteasomal degradation of VE-cadherin, which is preceded by its phosphorylation and internalization events associated with adherens junction disassembly and decreased EC barrier function.