Alix, making a link between apoptosis-linked gene-2, the endosomal sorting complexes required for transport, and neuronal death in vivo.
Alix/apoptosis-linked gene-2 (ALG-2)-interacting protein X is an adaptor protein involved in the regulation of the endolysosomal system through binding to endophilins and to endosomal sorting complexes required for transport (ESCRT) proteins, TSG101 and CHMP4b. It was first characterized as an interactor of ALG-2, a calcium-binding protein necessary for cell death, and several observations suggest a role for Alix in controlling cell death. We used electroporation in the chick embryo to test whether overexpressed wild-type or mutated Alix proteins influence cell death in vivo. We show that Alix overexpression is sufficient to induce cell death of neuroepithelial cells. This effect is strictly dependent on its capacity to bind to ALG-2. On the other hand, expression of Alix mutants lacking the ALG-2 or the CHMP4b binding sites prevents early programmed cell death in cervical motoneurons at day 4.5 of chick embryo development. This protection afforded by Alix mutants was abolished after deletion of the TSG101, but not of the endophilin, binding sites. Our results suggest that the interaction of the ALG-2/Alix complex with ESCRT proteins is necessary for naturally occurring death of motoneurons. Therefore, Alix represents a molecular link between the endolysosomal system and the cell death machinery.
Mahul-Mellier
Anne-Laure
AL
Institut 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.
Hemming
Fiona J
FJ
Blot
Béatrice
B
Fraboulet
Sandrine
S
Sadoul
Rémy
R
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D000870:Anterior Horn Cells / Q000166:cytology* / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D001665:Binding Sites; D001692:Biological Transport; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D002642:Chick Embryo; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000502:physiology; D018274:Electroporation; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism*; D051379:Mice; D046569:Neuroepithelial Cells / Q000166:cytology* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D014157:Transcription Factors / Q000502:physiology; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000502:physiology; D000099177:Tsg101 Protein
D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; D000099177:Tsg101 Protein; C490815:Pdcd6 protein, mouse; C492144:Pdcd6ip protein, mouse