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A glutathione-Nrf2-thioredoxin cross-talk ensures keratinocyte survival and efficient wound repair.
PLoS Genet. 12:e1005800 (2016)
The tripeptide glutathione is the most abundant cellular antioxidant with high medical relevance, and it is also required as a co-factor for various enzymes involved in the detoxification of reactive oxygen species and toxic compounds. However, its cell-type specific functions and its interaction with other cytoprotective molecules are largely unknown. Using a combination of mouse genetics, functional cell biology and pharmacology, we unraveled the function of glutathione in keratinocytes and its cross-talk with other antioxidant defense systems. Mice with keratinocyte-specific deficiency in glutamate cysteine ligase, which catalyzes the rate-limiting step in glutathione biosynthesis, showed a strong reduction in keratinocyte viability in vitro and in the skin in vivo. The cells died predominantly by apoptosis, but also showed features of ferroptosis and necroptosis. The increased cell death was associated with increased levels of reactive oxygen and nitrogen species, which caused DNA and mitochondrial damage. However, epidermal architecture, and even healing of excisional skin wounds were only mildly affected in the mutant mice. The cytoprotective transcription factor Nrf2 was strongly activated in glutathione-deficient keratinocytes, but additional loss of Nrf2 did not aggravate the phenotype, demonstrating that the cytoprotective effect of Nrf2 is glutathione dependent. However, we show that deficiency in glutathione biosynthesis is efficiently compensated in keratinocytes by the cysteine/cystine and thioredoxin systems. Therefore, our study highlights a remarkable antioxidant capacity of the epidermis that ensures skin integrity and efficient wound healing.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Ligase Modifier Subunit; Oxidative Stress; Glutathione Depletion; Epidermal Barrier; Thioredoxin Reductase; System X(c)(-); Cell-death; Mouse; Skin; Nrf2
ISSN (print) / ISBN
1553-7390
e-ISSN
1553-7404
Journal
PLoS Genetics
Quellenangaben
Volume: 12,
Issue: 1,
Article Number: e1005800
Publisher
Public Library of Science (PLoS)
Publishing Place
San Francisco
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Developmental Genetics (IDG)