Figure 6.

Neddylation and the HIF pathway. Under normoxic conditions, HIF-1α is hydroxylated by PHDs. In its hydroxylated form, HIF-1α is recognized by the Cul-2-Nedd8-pVHL complex, leading to polyubiquitination and degradation by the proteasome. Pharmacologic inhibition of Cul-2 neddylation using MLN4924 stabilizes cellular HIF-1α levels, leading to increased transcription of proresolving HIF target genes and increased barrier function. Loss of DEN-1 also positively influences barrier function of intestinal epithelial cells.