title: System x(c)- and thioredoxin reductase 1 cooperatively rescue glutathione deficiency.
abstract: 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 gamma-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.
authors.affiliation: Institute of Clinical Molecular Biology and Tumor Genetics, German Research Center for Environmental Health, 81377 Munich, Germany.
authors.forename: Pankaj Kumar
authors.initials: PK
authors.lastname: Mandal
authors.forename: Alexander
authors.initials: A
authors.lastname: Seiler
authors.forename: Tamara
authors.initials: T
authors.lastname: Perisic
authors.forename: Pirkko
authors.initials: P
authors.lastname: Kölle
authors.forename: Ana
authors.initials: A
authors.lastname: Banjac Canak
authors.forename: Heidi
authors.initials: H
authors.lastname: Förster
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lieberman
authors.forename: Shiro
authors.initials: S
authors.lastname: Bannai
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhlencordt
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D018920:Coculture Techniques; D003545:Cysteine / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D054481:Thioredoxin Reductase 1 / Q000172:deficiency / Q000378:metabolism*; D054482:Thioredoxin Reductase 2 / Q000172:deficiency / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D019328:Buthionine Sulfoximine; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; C516125:Txnrd1 protein, mouse; C516128:Txnrd2 protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D003545:Cysteine
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