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Alix, making a link between apoptosis-linked gene-2, the endosomal sorting complexes required for transport, and

Anne-Laure Mahul-Mellier1, Fiona J Hemming, Béatrice Blot

  • 1Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Neurodégénérescence et Plasticité, Equipe Mixte INSERM 0108, Universite Joseph Fourier, Grenoble I, F-38043 Grenoble, France.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|January 13, 2006
PubMed

Insights

Alix adaptor protein overexpression induces neuroepithelial cell death by binding ALG-2. Mutants protect motoneurons, revealing Alix

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Alix (apoptosis-linked gene-2 (ALG-2)-interacting protein X) is an adaptor protein regulating the endolysosomal system.
  • Alix interacts with endophilins and ESCRT proteins (TSG101, CHMP4b), and ALG-2, a calcium-binding protein involved in cell death.
  • Previous observations suggest Alix plays a role in controlling cell death pathways.

Purpose of the Study:

  • To investigate the in vivo role of Alix and its interactions in cell death using chick embryo electroporation.
  • To determine if Alix overexpression influences neuroepithelial cell death.
  • To elucidate the role of Alix-binding proteins (ALG-2, CHMP4b, TSG101, endophilin) in programmed motoneuron death.

Main Methods:

  • Overexpression of wild-type and mutated Alix proteins in chick embryos via electroporation.
  • Analysis of cell death in neuroepithelial cells and cervical motoneurons.
  • Assessment of binding site dependencies (ALG-2, CHMP4b, TSG101, endophilin) for Alix function.

Main Results:

  • Alix overexpression is sufficient to induce neuroepithelial cell death, dependent on ALG-2 binding.
  • Alix mutants lacking ALG-2 or CHMP4b binding sites protected cervical motoneurons from early programmed cell death.
  • Protection by Alix mutants was abolished by deleting the TSG101 binding site, but not the endophilin binding site.

Conclusions:

  • The ALG-2/Alix complex interaction with ESCRT proteins is crucial for naturally occurring motoneuron death.
  • Alix acts as a molecular bridge connecting the endolysosomal system to the cell death machinery.
  • Alix plays a dual role in cell death: inducing it via ALG-2 interaction and regulating it through ESCRT complex interactions.

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