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

J Biol Chem. 2017 Sep 29;292(39):16211-16220. doi: 10.1074/jbc.M116.769950. Epub 2017 Aug 10.

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.

Keywords: VEGF; autophagy; decorin; endothelial cell; proteoglycan.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinases / antagonists & inhibitors
  • AMP-Activated Protein Kinases / metabolism
  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Autophagy* / drug effects
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / agonists*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Cells, Cultured
  • Decorin / genetics
  • Decorin / metabolism*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Gene Expression Regulation / drug effects
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / chemistry
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • Receptors, Growth Factor / agonists*
  • Receptors, Growth Factor / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Signal Transduction* / drug effects
  • Sus scrofa
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DCN protein, human
  • Decorin
  • Kruppel-Like Transcription Factors
  • PEG3 protein, human
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • Receptors, Growth Factor
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • TFEB protein, human
  • decorin receptor
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • AMP-Activated Protein Kinases