Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria; Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Dermatology, Medical University of Vienna, Währinger Grürtel 18-20, 1090 Vienna, Austria; Christian Doppler Laboratory for the Biotechnology of Skin Aging, Vienna, Austria.
Int J Biochem Cell Biol. 2016 Dec;81(Pt B):375-382. doi: 10.1016/j.biocel.2016.10.006. Epub 2016 Oct 11.
Autophagy is a recycling program which allows cells to adapt to metabolic needs and to stress. Defects in autophagy can affect metabolism, aging, proteostasis and inflammation. Autophagy pathway genes, including autophagy related 7 (Atg7), have been associated with the regulation of skin pigmentation, and autophagy defects disturb the biogenesis and transport of melanosomes in melanocytes as well as transfer and processing of melanin into keratinocytes. We have previously shown that mice whose melanocytes or keratinocytes lack Atg7 (and thus autophagy) as a result of specific gene knockout still retained functioning melanosome synthesis and transfer, and displayed only moderate reduction of pigmentation. In cell culture the Atg7 deficient melanocytes were prone to premature senescence and dysregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. To elucidate the biochemical basis of this phenotype, we performed a study on global gene expression, protein secretion and phospholipid composition in Atg7 deficient versus Atg7 expressing melanocytes. In cell culture Atg7 deficient melanocytes showed a pro-inflammatory gene expression signature and secreted higher levels of C-X-C motif chemokine ligand -1,-2,-10 and -12 (Cxcl1, Cxcl2, Cxcl10, Cxcl12), which are implicated in the pathogenesis of pigmentary disorders and expressed higher amounts of matrix metalloproteinases -3 and -13 (Mmp3, Mmp13). The analysis of membrane phospholipid composition identified an increase in the arachidonic- to linoleic acid ratio in the autophagy deficient cells, as well as an increase in oxidized phospholipid species that act as danger associated molecular patterns (DAMPs). The secretion of inflammation related factors suggests that autophagy deficient melanocytes display a senescence associated secretory phenotype (SASP), and we propose oxidized lipid mediators as novel components of this SASP.
自噬是一种细胞内的回收程序，使细胞能够适应代谢需求和应激。自噬缺陷可能会影响代谢、衰老、蛋白质稳态和炎症。自噬途径基因，包括自噬相关 7（Atg7），与皮肤色素沉着的调节有关，自噬缺陷会干扰黑素细胞中黑素体的生物发生和运输，以及黑色素向角质细胞的转移和处理。我们之前已经表明，由于特定基因敲除，其黑素细胞或角质细胞缺乏 Atg7（因此缺乏自噬）的小鼠仍然保留了功能正常的黑素体合成和转移，并且仅表现出色素沉着的中度减少。在细胞培养中，Atg7 缺陷的黑素细胞容易发生过早衰老和核因子（红细胞衍生 2）样 2（Nrf2）信号的失调。为了阐明这种表型的生化基础，我们对 Atg7 缺陷型与 Atg7 表达型黑素细胞的全基因表达、蛋白质分泌和磷脂组成进行了研究。在细胞培养中，Atg7 缺陷的黑素细胞表现出促炎基因表达特征，并分泌更高水平的 C-X-C 基序趋化因子配体 -1、-2、-10 和 -12（Cxcl1、Cxcl2、Cxcl10、Cxcl12），这些因子与色素沉着障碍的发病机制有关，并表达更高水平的基质金属蛋白酶 -3 和 -13（Mmp3、Mmp13）。膜磷脂组成的分析表明，自噬缺陷细胞中的花生四烯酸与亚油酸的比值增加，以及氧化的磷脂种类增加，这些物质作为危险相关分子模式（DAMPs）发挥作用。炎症相关因子的分泌表明，自噬缺陷的黑素细胞表现出衰老相关的分泌表型（SASP），我们提出氧化脂质介质作为这种 SASP 的新成分。
