SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia

Cell. 2007 Nov 2;131(3):584-95. doi: 10.1016/j.cell.2007.08.045.

Abstract

SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1(-/-) embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1(-/-) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anemia / pathology
  • Animals
  • Apoptosis
  • Cell Hypoxia
  • Embryo, Mammalian / pathology
  • Endopeptidases / deficiency
  • Endopeptidases / metabolism*
  • Erythroid Precursor Cells / cytology
  • Erythropoiesis
  • Erythropoietin / biosynthesis
  • Erythropoietin / genetics
  • Fetus / cytology
  • Fetus / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Liver / cytology
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Processing, Post-Translational
  • Signal Transduction
  • Thermodynamics
  • Transcription, Genetic
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Erythropoietin
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Endopeptidases
  • Senp1 protein, mouse
  • Proteasome Endopeptidase Complex