The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway
The Transcription Factor p8 Regulates Autophagy in Response to Palmitic Acid Stress via a Mammalian Target of Rapamycin (mTOR)-independent Signaling Pathway
复制标题
转录因子 p8 通过哺乳动物雷帕霉素靶点 (mTOR) 独立信号通路调节自噬以响应棕榈酸应激
DOI：
10.1074/jbc.m115.675793
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发表时间：
2016-02-26
影响因子：
4.8
通讯作者：
Yang, Wei-Jun
中科院分区：
文献类型：
--
作者：
Jia, Sheng-Nan;Lin, Cheng;Yang, Wei-Jun
自噬是一种进化上保守的降解过程，允许细胞在许多生理情况下保持自稳。这一过程也是对内质网(ER)胁迫的一种必要的保护性反应，促进未折叠蛋白质的去除和降解。然而，关于自噬是如何在内质网压力下启动和调节的，我们知之甚少。在本研究中，我们鉴定了不同类型的人胃癌MKN45细胞对营养物质饥饿或脂毒诱导的应激反应的自噬，其中这些途径的调节分别是依赖于或非依赖于雷帕霉素(MTOR)的哺乳动物靶标。有趣的是，我们发现，在用棕榈酸处理的MKN45细胞中，压力诱导转录因子p8被增强以诱导脂毒性。此外，在慢病毒系统中观察到稳定高表达p8的MKN45细胞自噬增加，p8RNAi可阻断棕榈酸诱导的自噬。Western blotting分析表明，自噬分别受p8或mTOR调控，以响应蛋白激酶样内质网激酶/激活转录因子6介导的脂毒性内质网应激或Parkin介导的营养饥饿线粒体应激。此外，我们的结果表明，棕榈酸诱导的自噬不依赖于mTOR，但这一自噬途径是由p8通过P53和PKCα介导的信号在MKN45细胞中调节的。我们的发现为p8在调节由细胞中过量脂肪积累的脂毒性效应所诱导的自噬中的作用提供了洞察力。
Autophagy is an evolutionarily conserved degradative process that allows cells to maintain homoeostasis in numerous physiological situations. This process also functions as an essential protective response to endoplasmic reticulum (ER) stress, which promotes the removal and degradation of unfolded proteins. However, little is known regarding the mechanism by which autophagy is initiated and regulated in response to ER stress. In this study, different types of autophagy were identified in human gastric cancer MKN45 cells in response to the stress induced by nutrient starvation or lipotoxicity in which the regulation of these pathways is mammalian target of rapamycin (mTOR)-dependent or -independent, respectively. Interestingly, we found that p8, a stress-inducible transcription factor, was enhanced in MKN45 cells treated with palmitic acid to induce lipotoxicity. Furthermore, an increase in autophagy was observed in MKN45 cells stably overexpressing p8 using a lentivirus system, and autophagy induced by palmitic acid was blocked by p8 RNAi compared with the control. Western blotting analyses showed that autophagy was regulated by p8 or mTORin response to the protein kinase-like endoplasmic reticulum kinase/activating transcription factor 6-mediated ER stress of lipotoxicity or the parkin-mediated mitochondrial stress of nutrient starvation, respectively. Furthermore, our results indicated that autophagy induced by palmitic acid is mTOR-independent, but this autophagy pathway was regulated by p8 via p53-and PKC alpha-mediated signaling in MKN45 cells. Our findings provide insights into the role of p8 in regulating autophagy induced by the lipotoxic effects of excess fat accumulation in cells.