Hyperoxia augments ER-stress-induced cell death independent of BiP loss.
Cytotoxic reactive oxygen species are constantly formed as a by-product of aerobic respiration and are thought to contribute to aging and disease. Cells respond to oxidative stress by activating various pathways, whose balance is important for adaptation or induction of cell death. Our lab recently reported that BiP (GRP78), a proposed negative regulator of the unfolded protein response (UPR), declines during hyperoxia, a model of chronic oxidative stress. Here, we investigate whether exposure to hyperoxia, and consequent loss of BiP, activates the UPR or sensitizes cells to ER stress. Evidence is provided that hyperoxia does not activate the three ER stress receptors IRE1, PERK, and ATF6. Although hyperoxia alone did not activate the UPR, it sensitized cells to tunicamycin-induced cell death. Conversely, overexpression of BiP did not block hyperoxia-induced ROS production or increased sensitivity to tunicamycin. These findings demonstrate that hyperoxia and loss of BiP alone are insufficient to activate the UPR. However, hyperoxia can sensitize cells to toxicity from unfolded proteins, implying that chronic ROS, such as that seen throughout aging, could augment the UPR and, moreover, suggesting that the therapeutic use of hyperoxia may be detrimental for lung diseases associated with ER stress.
Gewandter
Jennifer S
JS
Department of Biochemistry and Biophysics, The University of Rochester, Rochester, NY 14642, USA.
Staversky
Rhonda J
RJ
O'Reilly
Michael A
MA
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D017382:Reactive Oxygen Species; D010100:Oxygen