title: Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction.
abstract: The mitochondria and the endoplasmic reticulum (ER) are two organelles that critically contribute to apoptosis induction. While it is established that they communicate, how cell death signals are transmitted from the mitochondria to the ER is unknown. Here, we show that the mitochondrial fission protein Fission 1 homologue (Fis1) conveys an apoptosis signal from the mitochondria to the ER by interacting with Bap31 at the ER and facilitating its cleavage into the pro-apoptotic p20Bap31. Exogenous apoptosis inducers likewise use this signalling route and induce the procession of Bap31. Moreover, we show that the recruitment of procaspase-8 to the Fis1-Bap31 platform is an early event during apoptosis induction. The association of procaspase-8 with the Fis1-Bap31 complex is dependent on the variant of death effector domain (vDED) in Bap31 and is required for the activation of procaspase-8. This signalling pathway establishes a feedback loop by releasing Ca(2+) from the ER that activates the mitochondria for apoptosis. Hence, the Fis1-Bap31 complex (ARCosome) that spans the mitochondria-ER interface serves as a platform to activate the initiator procaspase-8, and thereby bridges two critical organelles for apoptosis signalling.
authors.affiliation: Division of Experimental Medicine, Centre for Pharmacology and Therapeutics, Imperial College London, London, UK.
authors.forename: Ryota
authors.initials: R
authors.lastname: Iwasawa
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mahul-Mellier
authors.forename: Christoph
authors.initials: C
authors.lastname: Datler
authors.forename: Evangelos
authors.initials: E
authors.lastname: Pazarentzos
authors.forename: Stefan
authors.initials: S
authors.lastname: Grimm
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D010539:Permeability; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: C091247:BCAP31 protein, human; D017931:DNA Primers; C476525:FIS1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D053181:Caspase 8; D002118:Calcium