Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α

Mol Cell. 2011 Nov 4;44(3):476-90. doi: 10.1016/j.molcel.2011.08.033.

Abstract

Homeostatic control of oxygen availability allows cells to survive oxygen deprivation. Although the transcription factor hypoxia-inducible factor 1α (HIF-1α) is the main regulator of the hypoxic response, the upstream mechanisms required for its stabilization remain elusive. Here, we show that p75 neurotrophin receptor (p75(NTR)) undergoes hypoxia-induced γ-secretase-dependent cleavage to provide a positive feed-forward mechanism required for oxygen-dependent HIF-1α stabilization. The intracellular domain of p75(NTR) directly interacts with the evolutionarily conserved zinc finger domains of the E3 RING ubiquitin ligase Siah2 (seven in absentia homolog 2), which regulates HIF-1α degradation. p75(NTR) stabilizes Siah2 by decreasing its auto-ubiquitination. Genetic loss of p75(NTR) dramatically decreases Siah2 abundance, HIF-1α stabilization, and induction of HIF-1α target genes in hypoxia. p75(NTR-/-) mice show reduced HIF-1α stabilization, vascular endothelial growth factor (VEGF) expression, and neoangiogenesis after retinal hypoxia. Thus, hypoxia-induced intramembrane proteolysis of p75(NTR) constitutes an apical oxygen-dependent mechanism to control the magnitude of the hypoxic response.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Cell Hypoxia
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Oxygen / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational*
  • Protein Stability
  • Receptors, Nerve Growth Factor / chemistry
  • Receptors, Nerve Growth Factor / deficiency
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism*
  • Retinal Neovascularization / metabolism
  • Time Factors
  • Transfection
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Nerve Growth Factor
  • Ngfr protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Siah2 protein, mouse
  • Ubiquitin-Protein Ligases
  • Amyloid Precursor Protein Secretases
  • Proteasome Endopeptidase Complex
  • Oxygen