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 (p75NTR) 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 p75NTR 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. p75NTR stabilizes Siah2 by decreasing its autoubiquitination. Genetic loss of p75NTR dramatically decreases Siah2 abundance, HIF-1α stabilization, and induction of HIF-1α target genes in hypoxia. p75NTR−/− mice show reduced HIF-1α stabilization, vascular endothelial growth factor (VEGF) expression, and neoangiogenesis after retinal hypoxia. Thus, hypoxia-induced intramembrane proteolysis of p75NTR constitutes an apical oxygen-dependent mechanism to control the magnitude of the hypoxic response.
Graphical Abstract
Highlights
► Hypoxia induces γ-secretase-mediated, regulated intramembrane proteolysis of p75NTR ► p75NTR stabilizes the ubiquitin ligase Siah2 by decreasing its autoubiquitination ► p75NTR regulates HIF-1α stabilization in hypoxia ► p75NTR regulates neoangiogenesis and VEGF expression in retinal hypoxia in vivo