The Cystine/Glutamate Antiporter System x c − in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Abstract

The antiporter system x_c ⁻ imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system x_c ⁻ is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system x_c ⁻, including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system x_c ⁻. Moreover, the roles of system x_c ⁻ in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system x_c ⁻ inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System x_c ⁻ is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x_c ⁻ in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS. Antioxid. Redox Signal. 18, 522–555.

I. Introduction

• A. Oxidative stress and antioxidant defense

• B. GSH metabolism

• C. Glutamate: neurotransmission and neurotoxicity

II. The Cystine/Glutamate Antiporter System xc −

• A. Functional and pharmacological characteristics of system xc −

• B. The molecular biology of system xc −

• C. The phylogeny of xCT, the specific subunit of system xc −

• D. Regulation of system xc − by transcriptional regulation of its specific subunit xCT

• E. Regulation of system xc − activity by protein trafficking and protein modification

• F. Regulation of system xc − activity by substrate availability

III. Expression of System xc−In Vitro and In Vivo and Its Functional Consequences

• A. In the absence of disease, system xc− shows a rather restricted expression pattern in vivo

• B. System xc − is induced in most cultured cells

• C. The role of system xc − in the regulation of GSH synthesis, the extracellular redox milieu, and extracellular glutamate levels

• D. Oxidative glutamate toxicity—an in vitro paradigm for neuronal death induced by system xc− inhibition

IV. The Role of System xc − in Health and Disease

• A. System xc−in vivo—lessons from xCT-deficient mice

• B. The role of system xc − in the immune system and inflammation

• C. The role of system xc − in cancer and resistance against anti-cancer drugs

• D. System xc − and diseases of the eye

• E. The role of system xc − in diseases of the CNS

• F. The role of system xc − activity in memory and behavior

V. Conclusion