title: Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease.
abstract: NPGPx is a member of the glutathione peroxidase (GPx) family; however, it lacks GPx enzymatic activity due to the absence of a critical selenocysteine residue, rendering its function an enigma. Here, we show that NPGPx is a newly identified stress sensor that transmits oxidative stress signals by forming the disulfide bond between its Cys57 and Cys86 residues. This oxidized form of NPGPx binds to glucose-regulated protein (GRP)78 and forms covalent bonding intermediates between Cys86 of NPGPx and Cys41/Cys420 of GRP78. Subsequently, the formation of the disulfide bond between Cys41 and Cys420 of GRP78 enhances its chaperone activity. NPGPx-deficient cells display increased reactive oxygen species, accumulated misfolded proteins, and impaired GRP78 chaperone activity. Complete loss of NPGPx in animals causes systemic oxidative stress, increases carcinogenesis, and shortens life span. These results suggest that NPGPx is essential for releasing excessive ER stress by enhancing GRP78 chaperone activity to maintain physiological homeostasis.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wei
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Hsieh
authors.forename: Mei-I
authors.initials: MI
authors.lastname: Su
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Jiang
authors.forename: Pang-Hung
authors.initials: PH
authors.lastname: Hsu
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Lo
authors.forename: Jui-Yun
authors.initials: JY
authors.lastname: Weng
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Phang-lang
authors.initials: PL
authors.lastname: Chen
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.forename: Kuo-Fen
authors.initials: KF
authors.lastname: Lee
authors.forename: Ming-Daw
authors.initials: MD
authors.lastname: Tsai
authors.forename: Jin-Yuh
authors.initials: JY
authors.lastname: Shew
authors.forename: Wen-Hwa
authors.initials: WH
authors.lastname: Lee
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003545:Cysteine; D004249:DNA Damage; D004220:Disulfides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005979:Glutathione Peroxidase; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D004220:Disulfides; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C578349:NPGPx protein, mouse; D016877:Oxidants; D017382:Reactive Oxygen Species; D010544:Peroxidases; C558641:GPX7 protein, human; D005979:Glutathione Peroxidase; D003545:Cysteine