Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
Mol Cell. 2011 Nov 4;44(3):476-90. doi: 10.1016/j.molcel.2011.08.033.
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.
内稳态氧供应控制使细胞能够在缺氧环境下存活。虽然转录因子缺氧诱导因子 1α（HIF-1α）是缺氧反应的主要调节剂，但仍不清楚其稳定所需的上游机制。在这里，我们发现 p75 神经生长因子受体（p75（NTR））经历缺氧诱导的γ-分泌酶依赖性切割，提供了氧气依赖性 HIF-1α稳定所需的正反馈机制。p75（NTR）的细胞内域直接与 E3 RING 泛素连接酶 Siah2（七个缺席同源物 2）的进化保守锌指结构域相互作用，该结构域调节 HIF-1α的降解。p75（NTR）通过降低其自身泛素化来稳定 Siah2。p75（NTR）的遗传缺失显着降低 Siah2 的丰度、HIF-1α 的稳定以及缺氧诱导的 HIF-1α 靶基因的诱导。p75（NTR-/-）小鼠在视网膜缺氧后表现出 HIF-1α稳定、血管内皮生长因子（VEGF）表达和新生血管形成减少。因此，缺氧诱导的 p75（NTR）跨膜蛋白水解构成了一种顶端氧气依赖性机制，可控制缺氧反应的幅度。
