Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α.
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.
Pubmed ID: 22055192 RIS Download
Amino Acid Sequence | Amyloid Precursor Protein Secretases | Animals | Anoxia | Cell Hypoxia | Disease Models, Animal | HEK293 Cells | Humans | Hypoxia-Inducible Factor 1, alpha Subunit | Mice | Mice, Inbred C57BL | Mice, Knockout | Molecular Sequence Data | NIH 3T3 Cells | Oxygen | Proteasome Endopeptidase Complex | Protein Interaction Domains and Motifs | Protein Processing, Post-Translational | Protein Stability | Receptors, Nerve Growth Factor | Retinal Neovascularization | Time Factors | Transfection | Ubiquitin-Protein Ligases | Ubiquitination | Vascular Endothelial Growth Factor A