Mechanisms of heme oxygenase-1 gene regulation by heme-hemopexin

Heme-hemopexin binding to the hemopexin receptor causes the activation of a signaling network of three kinase cascades (PKC, NFκB, and JNK); heme uptake by endocytosis, and induction of heme oxygenase-1. We hypothesized that copper is required for heme oxygenase-1 regulation in response to heme uptake, as shown for iron uptake in yeast. My work with three copper chelators demonstrates that copper is needed for heme oxygenase-1 regulation by heme-hemopexin. Acidification of endosomes is shown to be required for heme oxygenase-1 regulation by heme-hemopexin. Heme is released via protonation of histidine residues that coordinate heme to hemopexin. Heme-hemopexin increases nuclear Nrf2 levels in a PKC α/βII dependent manner as does CoPP-hemopexin. However, this is insufficient for heme oxygenase-1 induction and heme released from hemopexin must reach the nucleus from the endosome. This relieves the repression by Bach1; then Nrf2 binds to MafK on the promoter and activates the heme oxygenase-1 gene.