Figure 8.

Proposed model for the protein kinase R (PKR)-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) activation in Leishmania infection. Internalized parasite signals through the endosomal compartment via TLR2 and induce activation of PKR by dimerization and subsequent autophosphorylation. Subsequently, we found that GSK3 phosphorylation is dependent of PKR signaling, allowing that not occur inhibition of Nrf2 through Neh6 inhibitory domain. This activation of Nrf2 is also dependent of Keap1 inhibition through of autophagic and PKR pathways. These mechanisms induce nuclear translocation Nrf2, increasing the gene expression of Sod1, Nrf2, and p62. The sequestosome-1 (p62) could be recruiting, together with processed LC3-II and Keap1 for autophagic vacuoles, allowing greater Nrf2 activation and inhibition of oxidative stress through antioxidant enzymes.