title: Ligand-dependent cleavage of the P75 neurotrophin receptor is necessary for NRIF nuclear translocation and apoptosis in sympathetic neurons.
abstract: 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.
authors.affiliation: Department of Biochemistry and Center for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
authors.forename: Rajappa S
authors.initials: RS
authors.lastname: Kenchappa
authors.forename: Niccolò
authors.initials: N
authors.lastname: Zampieri
authors.forename: Moses V
authors.initials: MV
authors.lastname: Chao
authors.forename: Philip A
authors.initials: PA
authors.lastname: Barker
authors.forename: Henry K
authors.initials: HK
authors.lastname: Teng
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Carter
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020800:Receptor, Nerve Growth Factor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases