Epidermal melanocytes are constantly exposed to environmental stressors such as ultraviolet light (UV) and chemotoxins. Several evolutionarily conversed survival mechanisms are deployed to ensure melanocyte recovery after damage including the unfolded protein response (UPR) and integrated stress response (ISR). The UPR/ISR promote restoration of homeostasis, by modulating transcription and translation as well as activating nuclear factor erythroid 2‐related factor 2 (NRF2)‐mediated antioxidant activity. If repair fails, the UPR/ISR either stimulate cell death, or adaptation that can lead to survival of damaged cells and promote disease. For example, the UPR/ISR may support melanomagenesis by allowing UV‐damaged, mutated cells to survive and adapt to a hostile tumor microenvironment that subjects cells to hypoxia, nutrient deprivation, and sub‐optimal pH. The UPR and ISR can also promote transcriptional changes that support tumor growth and/or metastasis. Furthermore, these pathways may also underlie acquisition of chemoresistance and modulation of protein expression that alters the efficacy of immunotherapies. UPR activation has also been implicated in the pathogenesis of vitiligo and may promote increased expression of chemokines such as interleukin 6 and interleukin 8 that trigger an autoimmune response against melanocytes. We herein review the potential roles of the UPR/ISR in the etiology of melanoma and vitiligo.

中文翻译：

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黑色素瘤和白癜风的未折叠蛋白和综合应激反应

表皮黑色素细胞不断暴露于环境压力源，如紫外线 (UV) 和化学毒素。部署了几种进化上相反的生存机制，以确保损伤后黑素细胞的恢复，包括未折叠蛋白反应 (UPR) 和综合应激反应 (ISR)。UPR/ISR 通过调节转录和翻译以及激活核因子红细胞 2 相关因子 2 (NRF2) 介导的抗氧化活性来促进体内平衡的恢复。如果修复失败，UPR/ISR 要么刺激细胞死亡，要么刺激导致受损细胞存活并促进疾病的适应。例如，UPR/ISR 可以通过允许紫外线损伤的突变细胞存活并适应使细胞缺氧、营养缺乏、和次优的 pH 值。UPR 和 ISR 还可以促进支持肿瘤生长和/或转移的转录变化。此外，这些途径也可能是化学抗性的获得和蛋白质表达调节的基础，这会改变免疫疗法的功效。UPR 激活也与白斑病的发病机制有关，并可能促进趋化因子（如白细胞介素 6 和白细胞介素 8）的表达增加，从而引发针对黑素细胞的自身免疫反应。我们在此回顾了 UPR/ISR 在黑色素瘤和白斑病病因学中的潜在作用。这些途径也可能是获得化学抗性和调节蛋白质表达的基础，从而改变免疫疗法的功效。UPR 激活也与白斑病的发病机制有关，并可能促进趋化因子（如白细胞介素 6 和白细胞介素 8）的表达增加，从而引发针对黑素细胞的自身免疫反应。我们在此回顾了 UPR/ISR 在黑色素瘤和白斑病病因学中的潜在作用。这些途径也可能是获得化学抗性和调节蛋白质表达的基础，从而改变免疫疗法的功效。UPR 激活也与白斑病的发病机制有关，并可能促进趋化因子（如白细胞介素 6 和白细胞介素 8）的表达增加，从而引发针对黑素细胞的自身免疫反应。我们在此回顾了 UPR/ISR 在黑色素瘤和白斑病病因学中的潜在作用。