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

Le Moan, N., Houslay, D.M., Christian, F. , Houslay, M.D. and Akassoglou, K. (2011) Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α. Molecular Cell, 44(3), pp. 476-490. (doi: 10.1016/j.molcel.2011.08.033)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Houslay, Professor Miles and Christian, Dr Frank
• Authors: Le Moan, N., Houslay, D.M., Christian, F., Houslay, M.D., and Akassoglou, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Molecular Cell
• ISSN: 1097-2765