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. 2018 Oct 10;5:242. doi: 10.3389/fvets.2018.00242

Figure 2.

Figure 2

Role of Nrf2 in heme and iron metabolism. Nrf2 is a master regulator of the antioxidant response induced by thiol-reactive substances, such as electrophilic reagents and heavy metals. In unstressed cells, Nrf2 is constitutively ubiquitinated by the Keap1-Cullin 3 ubiquitination complex and degraded by the 26S proteasome. Keap1 oxidation induces Nrf2 stabilization, nuclear translocation, heterodimerization with sMafs, and the transcriptional activation of target genes by binding to antioxidant response elements (AREs). An Nrf2 target gene, HO-1, degrades free heme into biliverdin, carbon monoxide and iron. HO-1 transcription is repressed by Bach1. Heme binding induces the nuclear export and degradation of Bach1. Free iron released from heme also regulates ROS production. Nrf2 induces the transcription of ferritin heavy chain (FTH1) and light chain (FTL) to store iron in the oxidized state and of ferroportin 1 (FPN1) to export intracellular labile iron.