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

Natacha Le Moan, Daniel Houslay, Frank Christian, Miles Houslay, Katerina Akassoglou

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)476-490
Number of pages15
JournalMolecular Cell
Volume44
Issue number3
DOIs
Publication statusPublished - 3 Nov 2011

Keywords

  • Hif1alpha
  • p75NTR
  • p75 neurotrophin receptor
  • E3 RING ubiquitin ligase
  • Siah2
  • hypoxia

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