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Kobayashi, S. ; Sato, M.* ; Kasakoshi, T.* ; Tsutsui, T.* ; Sugimoto, M.* ; Osaki, M.* ; Okada, F.* ; Igarashi, K.* ; Hiratake, J.* ; Homma, T.* ; Conrad, M. ; Fujii, J.* ; Soga, T.* ; Bannai, S.* ; Sato, H.*

Cystathionine is a novel substrate of cystine/glutamate transporter: Implications for immune function.

J. Biol. Chem. 290, 8778-8788 (2015)
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The cystine/glutamate transporter, designated as system xc-, is important for maintaining intracellular glutathione levels and extracellular redox balance. The substrate-specific component of system xc-, xCT, is strongly induced by various stimuli, including oxidative stress, whereas it is constitutively expressed only in specific brain regions and immune tissues such as thymus and spleen. While cystine and glutamate are the well-established substrates of system xc- and the knockout of xCT leads to alterations of extracellular redox balance, nothing is known about other potential substrates. We thus performed a comparative metabolite analysis of tissues from xCT-deficient and wild-type mice using capillary electrophoresis time-of-flight mass spectrometry. Although most of the analysed metabolites did not show significant alterations between xCT-deficient and wild-type mice, cystathionine emerged to be absent specifically in thymus and spleen of xCT-deficient mice. No expression of either cystathionine β-synthase or cystathionine γ-lyase was observed in thymus and spleen of mice. In embryonic fibroblasts derived from wild-type embryos, cystine uptake was significantly inhibited by cystathionine in a concentration-dependent manner. Wild-type cells showed an intracellular accumulation of cystathionine when incubated in cystathionine-containing buffer, which concomitantly stimulated an increased release of glutamate into the extracellular space. By contrast, none of these effects could be observed in xCT-deficient cells. Remarkably, unlike knockout cells, wild-type cells could be rescued from cystine deprivation-induced cell death by cystathionine supplementation. We thus conclude that cystathionine is a novel physiological substrate of system xc-, and that the accumulation of cystathionine in immune tissues is exclusively mediated by system xc-.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Amino Acid Transport ; Cystathionine ; Cystine ; Exchanger ; Glutamate ; Glutathione ; Oxidative Stress ; Substrate Specificity ; System Xc-; Human-diploid Fibroblasts; Amino-acid-transport; System X(c)(-); Oxidative-stress; Plasma-membrane; Exchange Transporter; L-glutamate; Cell-lines; L-cystine; Expression
Language english
Publication Year 2015
HGF-reported in Year 2015
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Journal Journal of Biological Chemistry, The
Quellenangaben Volume: 290, Issue: 14, Pages: 8778-8788 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Publishing Place Bethesda
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
POF-Topic(s) 30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500500-001
G-500500-004
PubMed ID 25713140
DOI 10.1074/jbc.M114.625053
WOS ID WOS:000352207100009
Scopus ID 84926430043
Erfassungsdatum 2015-02-27
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