Figure 5.

Oxidation of the Caenorhabditis elegans IRE-1 kinase domain inhibits canonical unfolded protein response (UPR) signaling and promotes an antioxidant response. High levels of hydrogen peroxide (H₂O₂) triggers oxidation of a conserved cysteine (red circle) in the activation loop in the kinase domain, which inhibits kinase activity and prevents activation of the RNase domain, preventing canonical UPR signaling. Dissociation of BiP from IRE-1 is normally associated with UPR induction, and BiP remains associated with oxidized IRE-1 [114]. Oxidation results in the recruitment of the scaffold TRF-1 and kinase NSY-1, which mediate initiation of an antioxidant transcriptional response through the transcription factor SKN-1.