Molecular Cell
Volume 44, Issue 3, 4 November 2011, Pages 476-490
Journal home page for Molecular Cell

Article
Oxygen-Dependent Cleavage of the p75 Neurotrophin Receptor Triggers Stabilization of HIF-1α

https://doi.org/10.1016/j.molcel.2011.08.033Get rights and content
Under an Elsevier user license
open archive

Summary

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.

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

Cited by (0)