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

Wei, Pei‐Chi; Hsieh, Yi Hsuan; Su, Mei; 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

doi:10.1016/j.molcel.2012.10.007

Cited by 128 publications

(160 citation statements)

References 48 publications

(54 reference statements)

Supporting

Mentioning

156

Contrasting

Order By: Relevance

“…Similar to the oxidative modifications we have described for yeast BiP, human BiP cysteines are susceptible to oxidation by glutathione (16), peroxide (10), and prone to formation of an intramolecular disulfide bond (10). As we observed for yeast BiP, oxidation of human BiP augments its polypeptide binding activity (10). However, the range of modifications detected on BiP orthologues extends beyond cysteine oxidation.…”

Section: Discussionmentioning

confidence: 82%

“…Alternatively, BiP senses fluctuations in ER peroxide levels, which have the potential to cause oxidative damage to folding polypeptides. In mammalian cells, BiP oxidation (and the corresponding increase in holdase activity) is a consequence of a redox relay initiated by peroxide-mediated oxidation of the stress sensor GPx7 (NPGPx) (10). For yeast BiP (also known as Kar2), we have shown its single cysteine (Cys-63) is susceptible to direct modification by peroxide, forming a sulfenic acid adduct.…”

mentioning

confidence: 95%

“…Oxidation of active site cysteines in the oxidoreductase PDI has been demonstrated to trigger a conformational change that exposes a hydrophobic patch to facilitate high chaperone activity (8). Similarly, oxidation of cysteine(s) in the Hsp70 chaperone BiP can augment BiP activity as a polypeptide holdase (9,10). …”

mentioning

confidence: 99%

See 2 more Smart Citations

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

Wang

Sevier

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Redox fluctuations within cells can be detrimental to cell function. To gain insight into how cells normally buffer against redox changes to maintain cell function, we have focused on elucidating the signaling pathways that serve to sense and respond to oxidative redox stress within the endoplasmic reticulum (ER) using yeast as a model system. Previously, we have shown that a cysteine in the molecular chaperone BiP, a Hsp70 molecular chaperone within the ER, is susceptible to oxidation by peroxide during ER-derived oxidative stress, forming a sulfenic acid (؊SOH) moiety. Here, we demonstrate that this same conserved BiP cysteine is susceptible also to glutathione modification (؊SSG). Glutathionylated BiP is detected both as a consequence of enhanced levels of cellular peroxide and also as a by-product of increased levels of oxidized glutathione (GSSG). Similar to sulfenylation, we observe glutathionylation decouples BiP ATPase and peptide binding activities, turning BiP from an ATP-dependent foldase into an ATP-independent holdase. We show glutathionylation enhances cell proliferation during oxidative stress, which we suggest relates to modified BiP's increased ability to limit polypeptide aggregation. We propose the susceptibility of BiP to modification with glutathione may serve also to prevent irreversible oxidation of BiP by peroxide.Cell homeostasis and numerous vital cell functions rely on the maintenance of a proper intracellular redox balance. Oxidative folding in the endoplasmic reticulum (ER) 2 is one intracellular system that is prone to disruption upon alterations in the redox poise. Insufficient oxidizing capacity in the ER leads to the accumulation of proteins in reduced non-native states (1, 2). Alternatively, an overly oxidizing ER results in cellular toxicity, likely caused in part by the mis-pairing of protein cysteine residues resulting from a decreased capacity to reduce nonnative disulfides (3, 4). Crucial for maintaining a continual flux of folding polypeptides through the ER are the systems that buffer against fluctuations in the ER redox environment.Recently, several proteins have been demonstrated to act as sensors of redox fluctuations in the ER. In a common theme, these proteins sense changes in the ER redox environment and respond with beneficial alterations in their enzymatic activities. The enzyme Ero1 is a major source of oxidizing equivalents in the ER, and Ero1 activity is coupled to the ER redox environment. When the ER balance shifts to overly oxidizing conditions, regulatory cysteine residues in Ero1 become oxidized to disulfides, which decreases Ero1 oxidase activity to help restore redox balance (5-7). In addition, sensors that cope with the potential for protein folding defects have emerged. These redox-dependent chaperones do not directly impact the flux of oxidizing equivalents, like Ero1, but rather are activated to help limit polypeptide aggregation during unfavorable redox conditions. Oxidation of active site cysteines in the oxidoreductase PDI has been demonstrated to...

show abstract

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 95%

See 1 more Smart Citation

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

Wang

Sevier

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In mammalian cells, there are three peroxidases located in the ER, namely glutathione peroxidase 7 (GPx7) (Wang, Zhang, Niu, Sitia, & Wang, 2014), glutathione peroxidase 8 (GPx8) (Ramming, Hansen, Nagata, Ellgaard, & Appenzeller‐Herzog, 2014), and peroxiredoxin 4 (Prx4) (Zito et al., 2010). Of these peroxidases, GPx7 plays a particularly crucial role as GPX7 ‐deficient cells display increased ROS levels and an accumulation of misfolded proteins (Peng et al., 2012; Wei et al., 2012); furthermore, GPX7 ‐knockout mice exhibit increased systemic oxidative stress, increased carcinogenesis, and shortened lifespan (Wei et al., 2012). …”

Section: Introductionmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

View full text Add to dashboard Cite

SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

show abstract

“…Whether H 2 O 2 that is derived from endogenous Ero1 is sufficient to trigger ER stress is questionable (Appenzeller-Herzog, 2011;Ramming et al, 2014). Interestingly, peroxide sensing or quenching by GPX7 (a GPX8-related ER peroxidase, also known as NPGPx) promotes cell survival by stimulating the ER chaperone BiP (also known as GRP78 and HSPA5) (Wei et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

154

137

View full text Add to dashboard Cite

In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

show abstract

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

Cited by 128 publications

References 48 publications

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

Formation and Reversibility of BiP Protein Cysteine Oxidation Facilitate Cell Survival during and post Oxidative Stress

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Redox controls UPR to control redox

Contact Info

Product

Resources

About