title: Changes in membrane lipids drive increased endocytosis following Fas ligation.
abstract: Once activated, some surface receptors promote membrane movements that open new portals of endocytosis, in part to facilitate the internalization of their activated complexes. The prototypic death receptor Fas (CD95/Apo1) promotes a wave of enhanced endocytosis that induces a transient intermixing of endosomes with mitochondria in cells that require mitochondria to amplify death signaling. This initiates a global alteration in membrane traffic that originates from changes in key membrane lipids occurring in the endoplasmic reticulum (ER). We have focused the current study on specific lipid changes occurring early after Fas ligation. We analyzed the interaction between endosomes and mitochondria in Jurkat T cells by nanospray-Time-of-flight (ToF) Mass Spectrometry. Immediately after Fas ligation, we found a transient wave of lipid changes that drives a subpopulation of early endosomes to merge with mitochondria. The earliest event appears to be a decrease of phosphatidylcholine (PC), linked to a metabolic switch enhancing phosphatidylinositol (PI) and phosphoinositides, which are crucial for the formation of vacuolar membranes and endocytosis. Lipid changes occur independently of caspase activation and appear to be exacerbated by caspase inhibition. Conversely, inhibition or compensation of PC deficiency attenuates endocytosis, endosome-mitochondria mixing and the induction of cell death. Deficiency of receptor interacting protein, RIP, also limits the specific changes in membrane lipids that are induced by Fas activation, with parallel reduction of endocytosis. Thus, Fas activation rapidly changes the interconversion of PC and PI, which then drives enhanced endocytosis, thus likely propagating death signaling from the cell surface to mitochondria and other organelles.
authors.affiliation: Italian Institute of Technology, Genoa, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Degli Esposti
authors.affiliation: Department of Drug Research and Evaluation, Istituto Superiore Sanita', Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.affiliation: Department of Drug Research and Evaluation, Istituto Superiore Sanita', Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tinari
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Agostina
authors.initials: A
authors.lastname: Longo
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Recalchi
authors.affiliation: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
authors.affiliation: Department of Drug Research and Evaluation, Istituto Superiore Sanita', Rome, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Misasi
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Tina
authors.initials: T
authors.lastname: Garofalo
authors.affiliation: Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161, Rome, Italy. maurizio.sorice@uniroma1.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sorice
mesh_terms: D020169:Caspases / Q000378:metabolism*; D004705:Endocytosis / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D013058:Mass Spectrometry; D008563:Membrane Lipids / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D008563:Membrane Lipids; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases
keywords: Cell death; Endosomes; Membrane lipids; Membrane traffic; Mitochondria