Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature

Thomas Neill, Eva Andreuzzi, Zi Xuan Wang, Stephen C. Peiper, Maurizo Mongiat, Renato V. Iozzo

Research output: Contribution to journalArticle

Abstract

Regulation of autophagy by proteolytically cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. Endorepellin is the C-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and induces autophagy in endothelial cells. To further investigate this property, we used NanoString, a digital PCR platform for measuring predefined transcripts in biological samples to analyze a custom subset of 95 autophagy-related genes in human umbilical vein endothelial cells treated with ultrapure human recombinant endorepellin. We discovered an endorepellin-evoked pro-autophagic and pro-mitophagic gene expression signatures, which included two coordinately up-regulated mitochondrial-associated genes encoding the E3 ubiquitin protein ligase Parkin and the tumor suppressor mitostatin. Induction of both proteins required the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGFR2). Furthermore, we discovered that endorepellin evoked mitochondrial depolarization in endothelial cells via a specific interaction between its two proximal LG1/2 domains and VEGFR2. We also found that following loss of membrane potential, mitostatin and parkin interact and that mitostatin associates with the established Parkin receptor mitofusin-2. In conclusion, we have identified a critical role for endorepellin in remodeling the autophagic transcriptome and influencing mitochondrial homeostasis.

Original languageEnglish
Pages (from-to)12137-12148
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number31
DOIs
Publication statusPublished - Jan 1 2018

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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