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Nucleophosmin is a novel Bax chaperone that regulates apoptotic cell death

L E Kerr1, J-L A Birse-Archbold, D M Short

  • 1Astellas CNS Research in Edinburgh, The University of Edinburgh, Edinburgh, UK. Lorraine.Kerr@ed.ac.uk

Oncogene
|October 31, 2006
PubMed

Insights

The molecular chaperone nucleophosmin binds to activated Bax, promoting its translocation to mitochondria and initiating apoptosis. Nucleophosmin knockdown reduces cell death, revealing a novel therapeutic target for apoptosis-related diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The proapoptotic protein Bax is crucial for intrinsic apoptosis but its activation and mitochondrial translocation are not fully understood.
  • Identifying factors that regulate Bax activity is essential for understanding cell death pathways.

Purpose of the Study:

  • To identify novel proteins that interact with Bax and regulate its apoptotic function.
  • To elucidate the molecular mechanism of Bax activation and mitochondrial translocation.

Main Methods:

  • Affinity chromatography using Bax peptides to identify binding partners.
  • Mass spectrometry (MALDI-TOF) for protein identification.
  • Co-immunoprecipitation and proximity assays to confirm protein interactions.
  • Confocal microscopy and RNA interference (RNAi) in cell-based models.
  • Subcellular fractionation in a mouse model of ischemic stroke.

Main Results:

  • Nucleophosmin was identified as a novel Bax-binding protein.
  • Nucleophosmin specifically binds to the activated conformation of Bax.
  • Nucleophosmin translocates from the nucleolus to the cytosol before Bax translocation to mitochondria.
  • Nucleophosmin knockdown attenuates apoptosis by inhibiting cytochrome c release and caspase activation.
  • Nucleophosmin translocation precedes Bax translocation in an ischemic stroke mouse model.

Conclusions:

  • Nucleophosmin acts as a key regulator of Bax activation and mitochondrial translocation.
  • This interaction initiates the intrinsic apoptotic pathway, leading to cell death.
  • Targeting the nucleophosmin-Bax interaction offers a potential therapeutic strategy for diseases involving aberrant apoptosis.

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