Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease

Pei Chi Wei, Yi Hsuan Hsieh, Mei I. Su, Xianzhi Jiang, Pang Hung Hsu, Wen Ting Lo, Jui Yun Weng, Yung Ming Jeng, Ju-Ming Wang, Phang lang Chen, Yi Cheng Chang, Kuo Fen Lee, Ming Daw Tsai, Jin Yuh Shew, Wen Hwa Lee

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68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)747-759
Number of pages13
JournalMolecular Cell
Volume48
Issue number5
DOIs
Publication statusPublished - 2012 Dec 14

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Glutathione Peroxidase
Disulfides
Oxidative Stress
Selenocysteine
Reactive Oxygen Species
Carcinogenesis
Homeostasis
Proteins
glucose-regulated proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Wei, P. C., Hsieh, Y. H., Su, M. I., Jiang, X., Hsu, P. H., Lo, W. T., ... Lee, W. H. (2012). Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease. Molecular Cell, 48(5), 747-759. https://doi.org/10.1016/j.molcel.2012.10.007
Wei, Pei Chi ; Hsieh, Yi Hsuan ; Su, Mei I. ; Jiang, Xianzhi ; Hsu, Pang Hung ; Lo, Wen Ting ; Weng, Jui Yun ; Jeng, Yung Ming ; Wang, Ju-Ming ; Chen, Phang lang ; Chang, Yi Cheng ; Lee, Kuo Fen ; Tsai, Ming Daw ; Shew, Jin Yuh ; Lee, Wen Hwa. / Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease. In: Molecular Cell. 2012 ; Vol. 48, No. 5. pp. 747-759.
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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.",
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Wei, PC, Hsieh, YH, Su, MI, Jiang, X, Hsu, PH, Lo, WT, Weng, JY, Jeng, YM, Wang, J-M, Chen, PL, Chang, YC, Lee, KF, Tsai, MD, Shew, JY & Lee, WH 2012, 'Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease', Molecular Cell, vol. 48, no. 5, pp. 747-759. https://doi.org/10.1016/j.molcel.2012.10.007

Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease. / Wei, Pei Chi; Hsieh, Yi Hsuan; Su, Mei I.; Jiang, Xianzhi; Hsu, Pang Hung; Lo, Wen Ting; Weng, Jui Yun; Jeng, Yung Ming; Wang, Ju-Ming; Chen, Phang lang; Chang, Yi Cheng; Lee, Kuo Fen; Tsai, Ming Daw; Shew, Jin Yuh; Lee, Wen Hwa.

In: Molecular Cell, Vol. 48, No. 5, 14.12.2012, p. 747-759.

Research output: Contribution to journalArticle

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AU - Wei, Pei Chi

AU - Hsieh, Yi Hsuan

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AU - Jiang, Xianzhi

AU - Hsu, Pang Hung

AU - Lo, Wen Ting

AU - Weng, Jui Yun

AU - Jeng, Yung Ming

AU - Wang, Ju-Ming

AU - Chen, Phang lang

AU - Chang, Yi Cheng

AU - Lee, Kuo Fen

AU - Tsai, Ming Daw

AU - Shew, Jin Yuh

AU - Lee, Wen Hwa

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Y1 - 2012/12/14

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