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

研究成果: Article

68 引文 (Scopus)

摘要

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.

原文English
頁(從 - 到)747-759
頁數13
期刊Molecular Cell
48
發行號5
DOIs
出版狀態Published - 2012 十二月 14

指紋

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

引用此文

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. 於: Molecular Cell. 2012 ; 卷 48, 編號 5. 頁 747-759.
@article{8cc0ca88220d4339a566c7c66bcf52dd,
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.",
author = "Wei, {Pei Chi} and Hsieh, {Yi Hsuan} and Su, {Mei I.} and Xianzhi Jiang and Hsu, {Pang Hung} and Lo, {Wen Ting} and Weng, {Jui Yun} and Jeng, {Yung Ming} and Ju-Ming Wang and Chen, {Phang lang} and Chang, {Yi Cheng} and Lee, {Kuo Fen} and Tsai, {Ming Daw} and Shew, {Jin Yuh} and Lee, {Wen Hwa}",
year = "2012",
month = "12",
day = "14",
doi = "10.1016/j.molcel.2012.10.007",
language = "English",
volume = "48",
pages = "747--759",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",

}

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, 卷 48, 編號 5, 頁 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.

於: Molecular Cell, 卷 48, 編號 5, 14.12.2012, p. 747-759.

研究成果: Article

TY - JOUR

T1 - Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease

AU - Wei, Pei Chi

AU - Hsieh, Yi Hsuan

AU - Su, Mei I.

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

PY - 2012/12/14

Y1 - 2012/12/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84870877138&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870877138&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2012.10.007

DO - 10.1016/j.molcel.2012.10.007

M3 - Article

VL - 48

SP - 747

EP - 759

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 5

ER -