Molecular Cell
Volume 48, Issue 5, 14 December 2012, Pages 747-759
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Article
Loss of the Oxidative Stress Sensor NPGPx Compromises GRP78 Chaperone Activity and Induces Systemic Disease

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Summary

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.

Highlights

► NPGPx is an ER oxidative stress sensor by forming a Cys57/Cys86 disulfide bond ► Activated NPGPx enhances GRP78 chaperone activity though Cys41/Cys420 formation ► Dysfunction of NPGPx attenuates GRP78 to resolve misfolded protein, and increases ROS ► NPGPx deficiency generates excessive oxidative stress and causes systemic disease

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These authors contributed equally to this work