Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy.
Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy.
复制标题
DOI：
10.1074/jbc.m116.769950
复制
发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Iozzo RV
中科院分区：
文献类型：
--
作者：
Neill T;Sharpe C;Owens RT;Iozzo RV
大自噬是一种基本的和进化上保守的分解代谢过程，其根除真核细胞中受损和老化的大分子和细胞器。核心蛋白聚糖是一种典型的富含亮氨酸的小蛋白聚糖，在VEGF受体2（VEGFR2）信号转导下游启动一个持久的自噬程序，需要父系表达的基因3（PEG3）。我们已经发现，PEG 3是转录因子EB（TFEB）的上游转录调节因子，TFEB是一种溶酶体生物合成的主转录因子，用于核心蛋白聚糖诱导的内皮细胞自噬。我们发现PEG3在人脐静脉内皮细胞和PAER 2细胞中对TFEB转录诱导和核转位的功能需求。在机制上，抑制VEGFR2或AMP激活的蛋白激酶（AMPK），一个主要的核心蛋白聚糖激活的能量传感器激酶，防止核心蛋白聚糖诱发的TFEB诱导和核定位。总之，我们的研究结果表明，核心蛋白聚糖通过PEG 3和TFEB的促自噬生物活性的非经典（营养和能量独立）机制。
Macroautophagy is a fundamental and evolutionarily conserved catabolic process that eradicates damaged and aging macromolecules and organelles in eukaryotic cells. Decorin, an archetypical small leucine-rich proteoglycan, initiates a protracted autophagic program downstream of VEGF receptor 2 (VEGFR2) signaling that requires paternally expressed gene 3 (PEG3). We have discovered that PEG3 is an upstream transcriptional regulator of transcription factor EB (TFEB), a master transcription factor of lysosomal biogenesis, for decorin-evoked endothelial cell autophagy. We found a functional requirement of PEG3 for TFEB transcriptional induction and nuclear translocation in human umbilical vein endothelial and PAER2 cells. Mechanistically, inhibiting VEGFR2 or AMP-activated protein kinase (AMPK), a major decorin-activated energy sensor kinase, prevented decorin-evoked TFEB induction and nuclear localization. In conclusion, our findings indicate a non-canonical (nutrient- and energy-independent) mechanism underlying the pro-autophagic bioactivity of decorin via PEG3 and TFEB.