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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Cysteine
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DNA Damage
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Disulfides / metabolism
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Dose-Response Relationship, Drug
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress* / drug effects
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Endoplasmic Reticulum Stress* / genetics
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Fibroblasts / enzymology
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Fibroblasts / pathology
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Glutathione Peroxidase
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism*
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Homeostasis
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutagenesis, Site-Directed
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Mutation
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Oxidants / pharmacology
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Oxidation-Reduction
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Oxidative Stress* / drug effects
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Oxidative Stress* / genetics
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Peroxidases / genetics
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Peroxidases / metabolism*
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Protein Binding
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Protein Folding
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Proteostasis Deficiencies / enzymology*
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Proteostasis Deficiencies / genetics
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Proteostasis Deficiencies / pathology
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Reactive Oxygen Species / metabolism
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Signal Transduction* / drug effects
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Signal Transduction* / genetics
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Time Factors
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Transfection
Substances
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Carrier Proteins
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Disulfides
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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NPGPx protein, mouse
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Oxidants
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Reactive Oxygen Species
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Peroxidases
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GPX7 protein, human
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Glutathione Peroxidase
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Cysteine