Regulation of the unfolded protein response in yeast by oxidative stress

Abstract

In the unfolded protein response (UPR), Ire1 activates Hac1 to coordinate the transcription of hundreds of genes to mitigate ER stress. Recent work in Caenorhabditis elegans suggests that oxidative stress inhibits this canonical Ire1 signalling pathway, activating instead an antioxidant stress response. We sought to determine whether this novel mode of UPR function also existed in yeast, where Ire1 has been best characterized. We show that the yeast UPR is also subject to inhibition by oxidative stress. Inhibition is mediated by a single evolutionarily conserved cysteine, and affects both luminal and membrane pathways of Ire1 activation. In yeast, Ire1 appears dispensable for resistance to oxidative stress and, therefore, the physiological significance of this pathway remains to be demonstrated.

Translational Regulation of Pmt1 and Pmt2 by Bfr1 Affects Unfolded Protein O-Mannosylation

“…Osmolytes such as glycerol are often referred to as "chemical chaperones" and have been shown to increase protein stability and restore ER homeostasis [64]. Increased fluorescence of ER-GFP in oca1∆ and oca2∆ mutants might be explained by the recent finding that yeast UPR is inhibited by oxidative stress [65]. With important components of the oxidative stress response missing, yeast UPR could be more efficient in folding of the UPOM-reporter.…”

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

“…A phenotypic analysis suggests the potential for an analogous oxidant response pathway in yeast, although distinctions were observed. An attenuation of canonical UPR signaling was seen in the presence of arsenite (in worms and yeast) or peroxide (in yeast), and attenuation required the conserved cytoplasmic IRE1 cysteine [ 114 , 117 ]. The inhibitory effect of arsenite persisted even in the presence of established chemical inducers of the UPR, consistent with an inactivation of IRE1 kinase activity [ 114 , 117 ].…”

“…Yet, if and/or what alternative signaling is activated in yeast upon IRE1 modification remains to be elucidated. Hog1, the homologous yeast p38 MAP kinase, is activated by arsenite exposure [ 117 , 118 ]; yet, activation does not require the IRE1 cysteine [ 117 ]. The ultimate transcriptional output is also bound to be different.…”

“…In yeast, the transcription factor-based oxidative stress response is mediated through direct oxidation of the Yap family of transcription factors, which is distinct from the phosphorylation-based events described for SKN-1 [ 119 ]. Furthermore, no growth defect was observed for the yeast IRE1-C832S mutant in the presence of arsenite [ 117 ], leaving open the question as to what benefit may be conferred through the potential oxidation of yeast IRE1 Cys832.…”

“…Despite intriguing hints from reports focused on yeast and mammalian cells [ 115 , 117 ], whether sulfenylation is a conserved event used to alter the downstream signaling of IRE1 to mediate an antioxidant response remains an open question. Potential distinctions between the consequences observed for worm IRE1 sulfenylation and the potential mammalian response to IRE1 sulfenylation have been observed.…”