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The oxidative stress-inducible cystine/glutamate antiporter, system x −c : cystine supplier and beyond

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Abstract

The oxidative stress-inducible cystine/glutamate exchange system, system x −c , transports one molecule of cystine, the oxidized form of cysteine, into cells and thereby releases one molecule of glutamate into the extracellular space. It consists of two protein components, the 4F2 heavy chain, necessary for membrane location of the heterodimer, and the xCT protein, responsible for transport activity. Previously, system x −c has been regarded to be a mere supplier of cysteine to cells for the synthesis of proteins and the antioxidant glutathione (GSH). In that sense, oxygen, electrophilic agents, and bacterial lipopolysaccharide trigger xCT expression to accommodate with increased oxidative stress by stimulating GSH biosynthesis. However, emerging evidence established that system x −c may act on its own as a GSH-independent redox system by sustaining a redox cycle over the plasma membrane. Hallmarks of this cycle are cystine uptake, intracellular reduction to cysteine and secretion of the surplus of cysteine into the extracellular space. Consequently, increased levels of extracellular cysteine provide a reducing microenvironment required for proper cell signaling and communication, e.g. as already shown for the mechanism of T cell activation. By contrast, the enhanced release of glutamate in exchange with cystine may trigger neurodegeneration due to glutamate-induced cytotoxic processes. This review aims to provide a comprehensive picture from the early days of system x −c research up to now.

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Acknowledgments

The authors would like to thank Prof. Bannai for critically reading the manuscript. The work was supported by the Deutsche Forschungsgemeinschaft (DFG) (CO 291/2-2), the DFG-Priority Programme SPP1190 to MC, a JSPS Japan and Germany Bilateral Joint Research Project and a Grant-in-aid for scientific research to HS and a JSPS travel fellowship to MC.

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Authors and Affiliations

  1. DZNE, German Center for Neurodegenerative Diseases, Munich, 80336, Munich, Germany

    Marcus Conrad

  2. Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany

    Marcus Conrad

  3. Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata University, Tsuruoka 1-23, Yamagata, 997-8555, Japan

    Hideyo Sato

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  1. Marcus Conrad
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  2. Hideyo Sato
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Correspondence to Marcus Conrad or Hideyo Sato.

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Conrad, M., Sato, H. The oxidative stress-inducible cystine/glutamate antiporter, system x −c : cystine supplier and beyond. Amino Acids 42, 231–246 (2012). https://doi.org/10.1007/s00726-011-0867-5

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  • DOI: https://doi.org/10.1007/s00726-011-0867-5

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