title: Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis.
abstract: Ultraviolet (UV) B irradiation can severely damage the skin and even induce tumorigenesis. It exerts its effects by direct DNA modification and by formation of reactive oxygen species (ROS). We developed a strategy to genetically activate target gene expression of the transcription factor NF-E2-related factor 2 (Nrf2) in keratinocytes in vivo based on expression of a constitutively active Nrf2 mutant. Activation of Nrf2 target genes strongly reduced UVB cytotoxicity through enhancement of ROS detoxification. Remarkably, the protective effect was extended to neighboring cells. Using different combinations of genetically modified mice, we demonstrate that Nrf2 activates the production, recycling, and release of glutathione and cysteine by suprabasal keratinocytes, resulting in protection of basal cells in a paracrine, glutathione/cysteine-dependent manner. Most importantly, we found that endogenous Nrf2 controls selective protection of suprabasal keratinocytes from UVB-induced apoptosis through activation of cytoprotective genes. This finding explains the preferential UVB-induced apoptosis of basal cells, which is important for elimination of mutated stem cells as well as for preservation of skin integrity. Taken together, our results identify Nrf2 as a key regulator in the UV response of the skin.
authors.affiliation: Department of Biology, Institute of Cell Biology, ETH Zurich, Zurich, Switzerland. matthias.schaefer@cell.biol.ethz.ch
authors.forename: Matthias
authors.initials: M
authors.lastname: Schäfer
authors.forename: Sabine
authors.initials: S
authors.lastname: Dütsch
authors.forename: Ulrich
authors.initials: U
authors.lastname: auf dem Keller
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Navid
authors.forename: Agatha
authors.initials: A
authors.lastname: Schwarz
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D019610:Cytoprotection / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D005978:Glutathione