Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis
Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis
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DOI：
10.1101/gad.568810
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发表时间：
2010-05-15
影响因子：
10.5
通讯作者：
Werner, Sabine
中科院分区：
文献类型：
--
作者：
Schaefer, Matthias;Duetsch, Sabine;Werner, Sabine
紫外线（UV）B照射可严重损伤皮肤，甚至诱发肿瘤发生。它通过直接修饰DNA和形成活性氧（ROS）发挥作用。我们开发了一种策略，遗传激活靶基因表达的转录因子NF-E2相关因子2（Nrf 2）在角质形成细胞在体内的基础上表达的组成型活性Nrf 2突变体。Nrf 2靶基因的激活通过增强ROS解毒而强烈降低UVB的细胞毒性。值得注意的是，这种保护作用扩展到了邻近的细胞。使用不同组合的转基因小鼠，我们证明，Nrf 2激活生产，回收和释放谷胱甘肽和半胱氨酸的基底上角质形成细胞，导致保护基底细胞的旁分泌，谷胱甘肽/半胱氨酸依赖的方式。最重要的是，我们发现内源性Nrf 2通过激活细胞保护基因来控制基底层上角质形成细胞对UVB诱导的细胞凋亡的选择性保护。这一发现解释了UVB诱导的基底细胞优先凋亡，这对于消除突变的干细胞以及保持皮肤完整性是重要的。综上所述，我们的研究结果将Nrf 2确定为皮肤UV响应的关键调节因子。
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.