Redox regulation by glutathione needs enzymes

Berndt, Carsten; Lillig, Christopher Horst; Flohé, Leopold

doi:10.3389/fphar.2014.00168

Cited by 76 publications

(63 citation statements)

References 43 publications

(49 reference statements)

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“…3). Notably, the relevance of GSSG as a physiological oxidant has been a point of debate in the literature; specifically, it has been noted that given a typical cysteine pK a , a substantial ϳ100-fold change in the ratio of GSSG to GSH in cells would need to occur for GSSG to mediate significant thiol oxidation (35,36). However, these arguments center primarily on the requirements for glutathionylation of cytoplasmic proteins, where the resting GSSG/GSH ratio has been measured at 1:30 to 1:100 (15).…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Sevier

2016

Journal of Biological Chemistry

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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...

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Section: Discussionmentioning

confidence: 99%

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

Wang

Sevier

2016

Journal of Biological Chemistry

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“…ROS scavenging is controlled by a set of enzymes. The main cellular redox couple, GSH/ GSSG, during redox regulation is highly controlled, especially by GSH peroxidases or members of the thioredoxin family of proteins (Berndt et al, 2014). Oxido-reductases of the thioredoxin family (redoxins) -thioredoxins, glutaredoxins, and peroxiredoxins -occur in all organisms and in all cell compartments.…”

Section: Reversible Thiol Modifications and Redoxin Targetsmentioning

confidence: 99%

Cytosolic thiol switches regulating basic cellular functions: GAPDH as an information hub?

Hildebrandt¹,

Knuesting²,

Berndt³

et al. 2015

Biological Chemistry

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143

131

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Cytosolic glyceraldehyde 3-phosphate dehydrogenase (GAPDH, E.C. 1.2.1.12) is present in all organisms and catalyzes the oxidation of triose phosphate during glycolysis. GAPDH is one of the most prominent cellular targets of oxidative modifications when reactive oxygen and nitrogen species are formed during metabolism and under stress conditions. GAPDH harbors a strictly conserved catalytic cysteine, which is susceptible to a variety of thiol modifications, including S-sulfenylation, S-glutathionylation, S-nitrosylation, and S-sulfhydration. Upon reversible oxidative thiol modification of GAPDH, glycolysis is inhibited leading to a diversion of metabolic flux through the pentose-phosphate cycle to increase NADPH production. Furthermore, oxidized GAPDH may adopt new functions in different cellular compartments including the nucleus, as well as in new microcompartments associated with the cytoskeleton, mitochondria and plasma membrane. This review focuses on the recently discovered mechanism underlying the eminent reactivity between GAPDH and hydrogen peroxide and the subsequent redox-dependent moonlighting functions discriminating between the induction either of adaptive responses and adjustment of metabolism or of cell death in yeast, plants, and mammals. In light of the summarized results, cytosolic GAPDH might function as a sensor for redox signals and an information hub to transduce these signals for appropriate responses.

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“…ROS generation precedes all occurrence in intracellular informational succession of events first of all calcium maintenance [26]. Besides ROS can simulate action of agonists [27], they regulate enzyme activity [28,29]. We show that cellular reply to a regulator and the level of intracellular calcium depended on ROS presence.…”

mentioning

confidence: 77%