Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 14, Pages 8778-8788Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.625053
Keywords
-
Categories
Funding
- Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from the Japan Society for the Promotion of Sciences
- Naito Foundation
- Collaborative Research Program of the Institute for Chemical Research, Kyoto University [2013-43]
- Grants-in-Aid for Scientific Research [22134007] Funding Source: KAKEN
Ask authors/readers for more resources
The cystine/glutamate transporter, designated as system x(c)(-), is important for maintaining intracellular glutathione levels and extracellular redox balance. The substrate-specific component of system x(c)(-), 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 the thymus and spleen. Although cystine and glutamate are the well established substrates of system x(c)(-) 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 analyzed metabolites did not show significant alterations between xCT-deficient and wild-type mice, cystathionine emerged as being absent specifically in the thymus and spleen of xCT-deficient mice. No expression of either cystathionine beta-synthase or cystathionine gamma-lyase was observed in the 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 knock-out 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 x(c)(-) and that the accumulation of cystathionine in immune tissues is exclusively mediated by system x(c)(-).
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available