Cu, Zn superoxide dismutase and NADP(H) homeostasis are required for tolerance of endoplasmic reticulum stress in Saccharomyces cerevisiae.
Genome-wide screening for sensitivity to chronic endoplasmic reticulum (ER) stress induced by dithiothreitol and tunicamycin (TM) identified mutants deleted for Cu, Zn superoxide dismutase (SOD) function (SOD1, CCS1) or affected in NADPH generation via the pentose phosphate pathway (TKL1, RPE1). TM-induced ER stress led to an increase in cellular superoxide accumulation and an increase in SOD1 expression and Sod1p activity. Prior adaptation of the hac1 mutant deficient in the unfolded protein response (UPR) to the superoxide-generating agent paraquat reduced cell death under ER stress. Overexpression of the ER oxidoreductase Ero1p known to generate hydrogen peroxide in vitro, did not lead to increased superoxide levels in cells subjected to ER stress. The mutants lacking SOD1, TKL1, or RPE1 exhibited decreased UPR induction under ER stress. Sensitivity of the sod1 mutant to ER stress and decreased UPR induction was partially rescued by overexpression of TKL1 encoding transketolase. These data indicate an important role for SOD and cellular NADP(H) in cell survival during ER stress, and it is proposed that accumulation of superoxide affects NADP(H) homeostasis, leading to reduced UPR induction during ER stress.
Tan
Shi-Xiong
SX
Ramaciotti Centre for Gene Function Analysis, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Teo
Mariati
M
Lam
Yuen T
YT
Dawes
Ian W
IW
Perrone
Gabriel G
GG
D002470:Cell Survival; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D005978:Glutathione / Q000378:metabolism; D006023:Glycoproteins / Q000502:physiology; D006706:Homeostasis; D018832:Molecular Chaperones / Q000235:genetics; D009249:NADP / Q000378:metabolism / Q000502:physiology*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000502:physiology; D010100:Oxygen / Q000502:physiology; D010427:Pentose Phosphate Pathway / Q000235:genetics; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014174:Transketolase / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
C491960:CCS1 protein, S cerevisiae; D006023:Glycoproteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D014415:Tunicamycin; D009249:NADP; D013482:Superoxide Dismutase; D050862:Oxidoreductases Acting on Sulfur Group Donors; C113186:ERO1 protein, S cerevisiae; D014174:Transketolase; D005978:Glutathione; D010100:Oxygen; D004229:Dithiothreitol