Lysosomes Support the Degradation, Signaling, and Mitochondrial Metabolism Necessary for Human Epidermal Differentiation.
Lysosomes Support the Degradation, Signaling, and Mitochondrial Metabolism Necessary for Human Epidermal Differentiation.
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DOI：
10.1016/j.jid.2018.02.035
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Ridky TW
中科院分区：
文献类型：
--
作者：
Monteleon CL;Agnihotri T;Dahal A;Liu M;Rebecca VW;Beatty GL;Amaravadi RK;Ridky TW
角质形成细胞在表皮分化过程中经历显著的结构重塑，包括蛋白质组的广泛转化以及总细胞生物量的减少。这表明细胞内蛋白质和细胞器的消化是角质形成细胞分化所必需的。在这里，我们使用遗传学和药理学的方法来证明，自噬和溶酶体功能所需的角质形成细胞分化的器官型人类皮肤。mTOR信号传导和线粒体氧化代谢需要溶酶体活性。反过来，作为氧化磷酸化的天然副产物产生的线粒体活性氧（mtROS）是角质形成细胞分化所必需的。最后，用外源性ROS治疗挽救了溶酶体抑制的角质形成细胞的分化缺陷。这些发现强调了溶酶体和线粒体之间的相互关系，其中溶酶体支持线粒体代谢和相关的线粒体ROS的产生。mtROS释放到基底层上角质形成细胞的细胞质中，触发表皮分化所必需的自噬和溶酶体介导的降解。由于有缺陷的溶酶体依赖性自噬与常见的皮肤病包括银屑病和特应性皮炎相关，因此更好地理解溶酶体在表皮稳态中的作用可能会指导未来的治疗策略。
Keratinocytes undergo significant structural remodeling during epidermal differentiation, including a broad transformation of the proteome coupled with a reduction in total cellular biomass. This suggests that intracellular digestion of proteins and organelles is necessary for keratinocyte differentiation. Here, we use both genetic and pharmacologic approaches to demonstrate that autophagy and lysosomal functions are required for keratinocyte differentiation in organotypic human skin. Lysosomal activity was required for mTOR signaling and mitochondrial oxidative metabolism. In turn, mitochondrial reactive oxygen species (mtROS), produced as a natural byproduct of oxidative phosphorylation, were necessary for keratinocyte differentiation. Finally, treatment with exogenous ROS rescued the differentiation defect in lysosome-inhibited keratinocytes. These findings highlight a reciprocal relationship between lysosomes and mitochondria, in which lysosomes support mitochondrial metabolism and the associated production of mtROS. The mtROS released to the cytoplasm in suprabasal keratinocytes triggers autophagy and lysosome-mediated degradation necessary for epidermal differentiation. As defective lysosome dependent autophagy is associated with common skin diseases including psoriasis and atopic dermatitis, a better understanding of the role of lysosomes in epidermal homeostasis may guide future therapeutic strategies.
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