Amino Acids

, Volume 42, Issue 1, pp 231–246 | Cite as

The oxidative stress-inducible cystine/glutamate antiporter, system xc: cystine supplier and beyond

Review Article


The oxidative stress-inducible cystine/glutamate exchange system, system xc, 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 xc 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 xc 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 xc research up to now.


4F2 Cystine/cysteine redox cycle Glutamate Glutathione Slc7a11 xCT 



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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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.DZNE, German Center for Neurodegenerative Diseases, MunichMunichGermany
  2. 2.Helmholtz Center Munich, German Research Center for Environmental Health, Institute of Developmental GeneticsNeuherbergGermany
  3. 3.Department of Food and Applied Life SciencesFaculty of Agriculture, Yamagata UniversityYamagataJapan

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