Neill Thomas, Sharpe Catherine, Owens Rick T, Iozzo Renato V
From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and.
LifeCell Corporation, Branchburg, New Jersey 08876.
J Biol Chem. 2017 Sep 29;292(39):16211-16220. doi: 10.1074/jbc.M116.769950. Epub 2017 Aug 10.
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.
巨自噬是一种基本且在进化上保守的分解代谢过程，可清除真核细胞中受损和衰老的大分子及细胞器。核心蛋白聚糖是一种典型的富含亮氨酸的小分子蛋白聚糖，它在血管内皮生长因子受体2（VEGFR2）信号传导下游启动一个持久的自噬程序，该程序需要父系表达基因3（PEG3）。我们发现，对于核心蛋白聚糖诱导的内皮细胞自噬，PEG3是溶酶体生物合成的主要转录因子转录因子EB（TFEB）的上游转录调节因子。我们发现PEG3对于人脐静脉内皮细胞和PAER2细胞中TFEB的转录诱导和核转位具有功能需求。从机制上讲，抑制VEGFR2或AMP激活的蛋白激酶（AMPK）（一种主要的由核心蛋白聚糖激活的能量感应激酶）可阻止核心蛋白聚糖诱导的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PEG3和TFEB发挥促自噬生物活性的潜在机制是非经典的（不依赖营养和能量）。
