Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy

Abstract

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.

Catabolic degradation of endothelial VEGFA via autophagy

“…We found that turning on AMPK via AICAR was sufficient to increase Peg3 (Fig. 1B,D), a master autophagic regulator induced by decorin (20,28,46), and simultaneously decrease intracellular VEGFA with a t1/2 of 2.6 h ( Fig. 1B,E).…”

“…A hallmark of decorin bioactivity is the dual property of being anti-angiogenic (13,15,27,32,86,87) and pro-autophagic (18,20,28, [46][47][48]. Moreover, the Dcn gene itself is an autophagic-inducible gene (88).…”

“…We discovered that Peg3 co-localizes and physically interacts with the autophagic regulators LC3 and Beclin 1 (44) in response to decorin and canonical autophagic stimuli in endothelial cells (20). Peg3 is necessary and sufficient to maintain and evoke BECN1, MAP1LC3A, and TFEB expression (20,28, 45,46), and drives LC3-positive autophagosome formation and autophagic flux (28). Moreover, we found that Peg3 is required for TSP-1 expression and secretion (28).…”

“…Our understanding of the molecular mechanisms of VEGFs regulating vascular homeostasis and angiogenesis has dramatically expanded in the past two decades (57,58). Given that decorin suppresses VEGFA with the concurrent induction of autophagy via VEGFR2/AMPKα/Peg3 in endothelial cells (20,28,46,48), we hypothesized these pathways could converge to catabolize intracellular VEGFA by autophagy as the mechanism for the oncosuppressive effects of decorin. In this study, we found that decorin evokes the protracted catabolism of intracellular VEGFA via endothelial cell autophagy in a VEGFR2/AMPK/Peg3 dependent manner as the functional apparatus to achieve angiostasis.…”

The Reactive Oxygen Species–Mitophagy Signaling Pathway Regulates Liver Endothelial Cell Survival During Ischemia/Reperfusion Injury

“…These studies suggest that failure to reactivate autophagy during reperfusion by activating KLF2 may regulate the increased cell death in LEC and is associated with microvascular dysfunction . It remains to be determined whether KLF2 activation is ROS‐dependent in LEC or whether alternative signaling pathways such as transcription factor EB, adenosine monophosphate–activated protein kinase, hypoxia inducible factor 1, and FOXO can also regulate LEC autophagy. Overall, our findings suggest that the early injury to LEC during IRI is linked to a disruption in the autophagy‐signaling pathway …”