p75 (the 75-kD neurotrophin receptor) binds various ligands, either alone or as part of a complex with other receptors, to regulate neuronal survival and various other processes. Under some circumstances, p75 signaling promotes neuronal survival; under others, it promotes apoptosis. The nuclear translocation of NRIF (neurotrophin receptor interacting factor), a protein that binds to the p75 intracellular domain, has been implicated in p75-mediated apoptosis; how NRIF gets to the nucleus has been unclear. Noting that phorbol ester treatment stimulates sequential p75 cleavage by TACE and γ-secretase, leading to release of its intracellular domain, Kenchappa et al. treated sympathetic neurons isolated from rat superior cervical ganglia with brain-derived neurotrophic factor (BDNF) or proBDNF. They found that these proapoptotic ligands promoted γ-secretase-dependent proteolysis of p75, whereas nerve growth factor (a survival-promoting ligand) did not. Ligand-dependent polyubiquitination and nuclear translocation of NRIF depended on γ-secretase activity, and immunoprecipitation analysis in both sympathetic neurons and a heterologous expression system indicated that p75 cleavage by γ-secretase facilitated the association of NRIF with the free intracellular domain. Likewise, BDNF- or proBDNF-mediated apoptosis depended on γ-secretase activity and was blocked by expression of a dominant-negative, γ-secretase-resistant p75 mutant, whereas expression of the free p75 intracellular domain was sufficient to elicit the polyubiquitination and nuclear translocation of NRIF and neuronal apoptosis. Apoptosis of superfluous sympathetic neurons occurs naturally during development, and p75 cleavage and nuclear localization of NRIF were apparent in neurons isolated during this developmental time period. Thus, the authors conclude that p75-mediated apoptosis in response to proapoptotic ligands depends on γ-secretase-dependent cleavage and release of the intracellular domain.
R. S. Kenchappa, N. Zampieri, M. V. Chao, P. A. Barker, H. K. Teng, B. L. Hempstead, B. D. Carter, Ligand-dependent cleavage of the p75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons. Neuron 50, 219-232 (2006). [Online Journal]