Plasmodium berghei-Mediated NRF2 Activation in Infected Hepatocytes Enhances Parasite Survival

Figure 1

Canonical and p62-dependent NRF2 activation. (a) In nonstressed cells, NRF2 is constantly expressed and bound to its negative regulator KEAP1, which acts as an adaptor protein for the interaction with the E3 ubiquitin ligase CUL3. CUL3 constantly ubiquitinates NRF2 targeting it for proteasomal degradation. (b) Canonical activation: oxidation of cysteine residues in KEAP1 by reactive oxygen species (ROS) leads to a conformational change of the protein. In the oxidized state KEAP1 cannot bind to NRF2 anymore, leading to the release of NRF2. Free NRF2 translocates into the nucleus where it heterodimerizes with small Maf (sMaf) proteins and activates transcription of genes containing an antioxidant response element (ARE) in their regulatory region. (c) p62-Dependent activation: NRF2 protein stability can also be regulated through p62 competing with NRF2 for interaction with KEAP1. KEAP1 has a higher affinity for p62 phosphorylated at serine 349 than for NRF2, leading to the release and therefore activation of NRF2. Schematic adapted from “Keap1-Nrf2 Pathway,” by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates.