Nrf2-dependent survival signaling during the unfolded protein response

The ability of cells to maintain homeostatic control in the face of cellular insults is critical in all aspects of multicellular life. The endoplasmic reticulum is exquisitely poised to sense and respond to many different cellular stresses that result from metabolic and protein folding imbalances. In response to stress originating from within this organelle, the PERK protein kinase, along with other proximal signaling molecules, initiates a program of transcriptional and translational regulation termed the Unfolded Protein Response. Upon activation, PERK phosphorylates the eukaryotic initiation factor 2α, that in turn attenuates global protein translation. This event leads to cell cycle arrest and the paradoxical upregulation in translation of specific transcripts. In the absence of PERK, cells are rendered acutely sensitive to the activation of the Unfolded Protein Response. This work describes the identification and characterization of a novel, pro-survival PERK substrate, the Nrf2 transcription factor. PERK-dependent phosphorylation releases Nrf2 from cytoplasmic sequestration and degradation, initiating a program of gene transcription that combats the cytotoxic accumulation of reactive oxygen species and depletion of glutathione that occurs during the Unfolded Protein Response