title: Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α.
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.
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Natacha
authors: N
authors: Le Moan
authors: Daniel M
authors: DM
authors: Houslay
authors: Frank
authors: F
authors: Christian
authors: Miles D
authors: MD
authors: Houslay
authors: Katerina
authors: K
authors: Akassoglou
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010100:Oxygen / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C533102:Siah2 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen