Ligand-Dependent Cleavage of the P75 Neurotrophin Receptor Is Necessary for NRIF Nuclear Translocation and Apoptosis in Sympathetic Neurons

Rajappa S. Kenchappa, Niccolò Zampieri, Moses V. Chao, Philip A. Barker, Henry K. Teng, Barbara L. Hempstead, Bruce D. Carter

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

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 γ-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 γ-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 γ-secretase dependent release of its ICD, which facilitates nuclear translocation of NRIF.

Original languageEnglish (US)
Pages (from-to)219-232
Number of pages14
JournalNeuron
Volume50
Issue number2
DOIs
StatePublished - Apr 20 2006

Keywords

  • CELLBIO
  • MOLNEURO
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

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