细胞生物学
低亲和力神经生长因子受体
细胞凋亡
受体
蛋白质水解
生物
神经营养素
细胞核
作者
Rajappa S. Kenchappa,Niccolò Zampieri,Moses V. Chao,Philip A. Barker,Henry K. Teng,Barbara L. Hempstead,Bruce D. Carter
出处
期刊:Neuron
[Elsevier]
日期:2006-04-20
卷期号:50 (2): 219-232
被引量:156
标识
DOI:10.1016/j.neuron.2006.03.011
摘要
The p75 neurotrophin receptor regulates neuronal survival, promoting it in some contexts yet activating apoptosis in others. The mechanism by which the receptor elicits these differential effects is poorly understood. Here, we demonstrate that p75 is cleaved by gamma-secretase in sympathetic neurons, specifically in response to proapoptotic ligands. This cleavage resulted in ubiquitination and subsequent nuclear translocation of NRIF, a DNA binding protein essential for p75-mediated apoptosis. Inhibition of gamma-secretase or expression of a mutant p75 resistant to this protease prevented receptor proteolysis, blocked NRIF nuclear entry, and prevented apoptosis. In contrast, overexpression of the p75 ICD resulted in NRIF nuclear accumulation and apoptosis. The receptor proteolysis and NRIF nuclear localization were also observed in vivo during naturally occurring cell death in the superior cervical ganglia. These results indicate that p75-mediated apoptosis requires gamma-secretase dependent release of its ICD, which facilitates nuclear translocation of NRIF.
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