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Mandal, P.K. ; Seiler, A. ; Perisic, T. ; Kölle, P.* ; Canak, A.B. ; Förster, H. ; Weiss, N.* ; Kremmer, E. ; Liebermann, M.W.* ; Bannai, S.* ; Kuhlencordt, P.* ; Sato, H.* ; Bornkamm, G.W. ; Conrad, M.

System xc− and thioredoxin reductase 1 cooperatively rescue glutathione deficiency.

J. Biol. Chem. 285, 22244-22253 (2010)
DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
GSH is the major antioxidant and detoxifier of xenobiotics in mammalian cells. A strong decrease of intracellular GSH has been frequently linked to pathological conditions like ischemia/reperfusion injury and degenerative diseases including diabetes, atherosclerosis, and neurodegeneration. Although GSH is essential for survival, the deleterious effects of GSH deficiency can often be compensated by thiol-containing antioxidants. Using three genetically defined cellular systems, we show here that forced expression of xCT, the substrate-specific subunit of the cystine/glutamate antiporter, in γ-glutamylcysteine synthetase knock-out cells rescues GSH deficiency by increasing cellular cystine uptake, leading to augmented intracellular and surprisingly high extracellular cysteine levels. Moreover, we provide evidence that under GSH deprivation, the cytosolic thioredoxin/thioredoxin reductase system plays an essential role for the cells to deal with the excess amount of intracellular cystine. Our studies provide first evidence that GSH deficiency can be rescued by an intrinsic genetic mechanism to be considered when designing therapeutic rationales targeting specific redox enzymes to combat diseases linked to GSH deprivation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Apoptosis; Glutathione; Oxidation Reduction; Oxidative Stress; Thiol; Cystine/Cysteine Cycle; Thioredoxin Reductase
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 285, Heft: 29, Seiten: 22244-22253 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
Institute of Molecular Immunology (IMI)
Institute of Developmental Genetics (IDG)