title: The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria.
abstract: Components of the death receptor-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIP(L)), a well-known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca(2+)-release as well as ER-mitochondria tethering was decreased in c-FLIP(-/-) mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIP(L) and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIP(L) emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, DAHFMO - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: E S
authors.initials: ES
authors.lastname: Marini
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, DAHFMO - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Giampietri
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, DAHFMO - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Petrungaro
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, DAHFMO - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Conti
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, DAHFMO - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Filippini
authors.affiliation: 1] Department of Biology, University of Padua, Padua, Italy [2] Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Scorrano
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, DAHFMO - Section of Histology and Medical Embryology, Sapienza University of Rome, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ziparo
mesh_terms: D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009185:Myelin Proteins; D000070798:Nogo Proteins; D015398:Signal Transduction
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8