Decorin causes autophagy in endothelial cells via Peg3

Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):E2582-91. doi: 10.1073/pnas.1305732110. Epub 2013 Jun 24.

Abstract

Soluble decorin affects the biology of several receptor tyrosine kinases by triggering receptor internalization and degradation. We found that decorin induced paternally expressed gene 3 (Peg3), an imprinted tumor suppressor gene, and that Peg3 relocated into autophagosomes labeled by Beclin 1 and microtubule-associated light chain 3. Decorin evoked Peg3-dependent autophagy in both microvascular and macrovascular endothelial cells leading to suppression of angiogenesis. Peg3 coimmunoprecipitated with Beclin 1 and LC3 and was required for maintaining basal levels of Beclin 1. Decorin, via Peg3, induced transcription of Beclin 1 and microtubule-associated protein 1 light chain 3 alpha genes, thereby leading to a protracted autophagic program. Mechanistically, decorin interacted with VEGF receptor 2 (VEGFR2) in a region overlapping with its natural ligand VEGFA, and VEGFR2 was required for decorin-evoked Beclin 1 and microtubule-associated protein 1 light chain 3 alpha expression as well as for Peg3 induction in endothelial cells. Moreover, decorin induced VEGFR2-dependent mitochondrial fragmentation and loss of mitochondrial membrane potential. Thus, we have unveiled a mechanism for a secreted proteoglycan in inducing Peg3, a master regulator of macroautophagy in endothelial cells.

Keywords: microvascular endothelial cells; porcine aortic endothelial cells; small leucine-rich proteoglycan.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / physiology*
  • Beclin-1
  • Cells, Cultured
  • Decorin / metabolism
  • Decorin / physiology*
  • Endothelium, Vascular / immunology*
  • Endothelium, Vascular / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Kruppel-Like Transcription Factors / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Protein Binding
  • Signal Transduction
  • Transcriptional Activation
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • DCN protein, human
  • Dcn protein, mouse
  • Decorin
  • Kruppel-Like Transcription Factors
  • MAP1LC3A protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • PEG3 protein, human
  • Peg3 protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2