FIGURE 6.

Part 1, mechanistic model of enhanced SUMOylation of IκBα during H/R. Part 2, initial exposure to hypoxia results in phosphorylation of IκBα at Ser³²/Ser³⁶ by Iκκβ. Part 3, phosphorylated IκBα is targeted for polyubiquitination by the E3 SCF ubiquitin-ligase and proteosomal degradation. Part 4, p65/p50 subunits of NFκB readily translocate to the nucleus and initiate transcriptional induction of NFκB-dependent genes, simultaneously p65 inducing expression of the IκBα gene. Part 5, the new generated unphosphorylated form of IκBα is transported back to the cytoplasm and available for SUMO-1 modification under the influence of Ado signaling. Part 6, the pool of SUMOylated IκBα increase with subsequent cycles of H/R under the influence increasing concentrations of Ado. High cytoplasmic concentrations of SUMOylated IκBα present as a result of H/R prevent further NFκB activation, because the SUMOylated IκBα is resistant to proteosomal degradation.