The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death

Banjac, Ana; Perisic, Tamara; Sato, Hiroki; Seiler, Alexander; Bannai, Shiro; Weiss, Norbert; Kölle, Petra; Tschoep, Katharina; Issels, Rolf D.; Daniel, Peter T.; Conrad, Marcus; Bornkamm, Georg W.

doi:10.1038/sj.onc.1210796

Cited by 270 publications

(223 citation statements)

References 42 publications

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“…NAC contributes to the maintenance of oxidative balance through the actions of the cysteine/cystine cycle. Like glutathione and GSSG, cysteine and cystine are coupled redox partners that help to prevent oxidative cellular dysfunction and injury (Iyer et al 2009;Banjac et al 2008;Vene et al 2011). Hence, the actions of NAC are multifold and interrelated, with the production of glutathione, the cysteine/cystine cycle, and the action of the glutamate/cystine antiporter contributing to the maintenance of oxidative balance and cellular function.…”

Section: Discussionmentioning

confidence: 99%

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

et al. 2013

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Maple syrup urine disease (MSUD) is an inborn metabolism error caused by a deficiency of branched-chain a-keto acid dehydrogenase complex activity. This blockage leads to an accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their corresponding a-keto and a-hydroxy acids. Previous reports suggest that MSUD patients are at high risk for chronic neuropsychiatric problems. Therefore, in this study, we assessed variables that suggest depressive-like symptoms (anhedonia as measured by sucrose intake, immobility during the forced swimming test and body and adrenal gland weight) in rats submitted to chronic administration of BCAA during development. Furthermore, we determined if these parameters were sensitive to imipramine and N-acetylcysteine/deferoxamine (NAC/DFX). Our results demonstrated that animals subjected to chronic administration of branched-chain amino acids showed a decrease in sucrose intake without significant changes in body weight. We also observed an increase in adrenal gland weight and immobility time during the forced swimming test. However, treatment with imipramine and NAC/DFX reversed these changes in the behavioral tasks. In conclusion, this study demonstrates a link between MSUD and depression in rats. Moreover, this investigation reveals that the antidepressant action of NAC/DFX and imipramine might be associated with their capability to maintain pro-/anti-oxidative homeostasis.

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Section: Discussionmentioning

confidence: 99%

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

et al. 2013

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“…In addition, Burkitt's Lymphoma cells overexpressing xCT were reported to become highly resistant to oxidative stress. Importantly, the cells exhibited H 2 O 2 resistance even in the absence of GSH synthesis (33), implying the importance of L-cysteine in the resistance to H 2 O 2 .…”

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confidence: 99%

The l-Cysteine/l-Cystine Shuttle System Provides Reducing Equivalents to the Periplasm in Escherichia coli

Ohtsu¹,

Wiriyathanawudhiwong²,

Morigasaki

et al. 2010

Journal of Biological Chemistry

111

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Intracellular thiols like L-cysteine and glutathione play a critical role in the regulation of cellular processes. Escherichia coli has multiple L-cysteine transporters, which export L-cysteine from the cytoplasm into the periplasm. However, the role of L-cysteine in the periplasm remains unknown. Here we show that an L-cysteine transporter, YdeD, is required for the tolerance of E. coli cells to hydrogen peroxide. We also present evidence that L-cystine, a product from the oxidation of L-cysteine by hydrogen peroxide, is imported back into the cytoplasm in a manner dependent on FliY, the periplasmic L-cystine-binding protein. Remarkably, this protein, which is involved in the recycling of the oxidized L-cysteine, is also found to be important for the hydrogen peroxide resistance of this organism. Furthermore, our analysis of the transcription of relevant genes revealed that the transcription of genes encoding FliY and YdeD is highly induced by hydrogen peroxide rather than by L-cysteine. These findings led us to propose that the inducible L-cysteine/Lcystine shuttle system plays an important role in oxidative stress tolerance through providing a reducing equivalent to the periplasm in E. coli.

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“…Both ROS production and the consequent antioxidant response are required for the release of mature, fully processed IL-1β (8). The antioxidant response is characterized by increased activity of the cystine/cysteine redox cycle (9). This cycle involves up-regulation of the functional subunit of the Xc − transporter xCT, which mediates the internalization of cystine, the oxidized form of the amino acid cysteine that prevails extracellularly (10); enhanced uptake of cystine; intracellular conversion to cysteine; and secretion of the reduced amino acid, resulting in a switch of the extracellular redox from the physiological oxidizing to a nonphysiological reduced state.…”

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confidence: 99%

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Tassi¹,

Carta²,

Delfino³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

131

159

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In healthy monocytes, Toll-like receptor (TLR) engagement induces production of reactive oxygen species (ROS), followed by an antioxidant response involved in IL-1β processing and secretion. Markers of the antioxidant response include intracellular thioredoxin and extracellular release of reduced cysteine. Cryopyrinassociated periodic syndromes (CAPS) are autoinflammatory diseases in which Nod-like receptor family pyrin domain-containing 3 (NLRP3) gene mutations lead to increased IL-1β secretion. We show in a large cohort of patients that IL-1β secretion by CAPS monocytes is much faster than that by healthy monocytes. This accelerated kinetics is caused by alterations in the basal redox state, as well as in the redox response to TLR triggering displayed by CAPS monocytes. Indeed, unstimulated CAPS monocytes are under a mild oxidative stress, with elevated levels of both ROS and antioxidants. The redox response to LPS is quickened, with early generation of the reducing conditions favoring IL-1β processing and secretion, and then rapidly exhausted. Therefore, secretion of IL-1β is accelerated, but reaches a plateau much earlier than in healthy controls. Pharmacologic inhibition of the redox response hinders IL-1β release, confirming the functional link between redox impairment and altered kinetics of secretion. Monocytes from patients with juvenile idiopathic arthritis display normal kinetics of redox response and IL-1β secretion, excluding a role of chronic inflammation in the alterations observed in CAPS. We conclude that preexisting redox alterations distinct from CAPS monocytes anticipate the pathogen-associated molecular pattern molecule-induced generation of the reducing environment favorable to inflammasome activation and IL-1β secretion.antioxidant response | inflammasome | reactive oxygen species | thioredoxin | autoinflammatory diseases

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The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death

Cited by 270 publications

References 42 publications

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

The l-Cysteine/l-Cystine Shuttle System Provides Reducing Equivalents to the Periplasm in Escherichia coli

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

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