Kenchappa Rajappa S, Zampieri Niccolò, Chao Moses V, Barker Philip A, Teng Henry K, Hempstead Barbara L, Carter Bruce D
Department of Biochemistry and Center for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
Neuron. 2006 Apr 20;50(2):219-32. doi: 10.1016/j.neuron.2006.03.011.
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.
p75神经营养因子受体调节神经元存活，在某些情况下促进存活，但在其他情况下激活细胞凋亡。该受体引发这些不同效应的机制尚不清楚。在这里，我们证明p75在交感神经元中被γ-分泌酶切割，特别是对促凋亡配体作出反应时。这种切割导致NRIF的泛素化及随后的核转位，NRIF是一种对p75介导的细胞凋亡至关重要的DNA结合蛋白。抑制γ-分泌酶或表达对该蛋白酶有抗性的突变p75可防止受体蛋白水解，阻止NRIF进入细胞核，并防止细胞凋亡。相反，p75胞内结构域（ICD）的过表达导致NRIF核积累和细胞凋亡。在颈上神经节自然发生的细胞死亡过程中，体内也观察到了受体蛋白水解和NRIF核定位。这些结果表明，p75介导的细胞凋亡需要其ICD通过γ-分泌酶依赖性释放，这有助于NRIF的核转位。
