title: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced mitochondrial pathway to apoptosis and caspase activation is potentiated by phospholipid scramblase-3.
abstract: Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) initiate pathways of cell death in which caspase activation is mediated either directly (without mitochondrial amplification), or indirectly via the release of apoptogenic factors from mitochondria. Phospholipid scramblases (PLS) are enzymes that play a key role in cellular function by inducing bidirectional movement of membrane lipids. Changes in mitochondrial membrane lipids, cardiolipin, are critical for mediating apoptotic response in many cell-types. PLS3 is a phospholipid scramblase that is localized to mitochondria and is thought to be involved in the regulation of apoptotic signals. Here we report that exogenous-expression of PLS3 enhances apoptotic death induced by TRAIL. This is acheived by potentiating the mitochondrial arm of the death pathway. Thereby, PLS3 expression facilitates changes in mitochondrial membrane lipids that promote the release of apoptogenic factors and consequent full activation and processing of the caspase-9 and effector caspase-3. Moreover, we show that knock-down of endogenous PLS3 suppresses TRAIL-induced changes in cardiolipin. Finally, we demonstrate that TRAIL-induced activation of PKC-delta mediates regulation of the PLS3-induced changes in cardiolipin.
authors.affiliation: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Ave, Boston, MA 02215, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ndebele
authors.forename: Philimon
authors.initials: P
authors.lastname: Gona
authors.forename: Tai-Guang
authors.initials: TG
authors.lastname: Jin
authors.forename: Nordine
authors.initials: N
authors.lastname: Benhaga
authors.forename: Anas
authors.initials: A
authors.lastname: Chalah
authors.forename: Mauro
authors.initials: M
authors.lastname: Degli-Esposti
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D002308:Cardiolipins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008563:Membrane Lipids / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D049294:Phospholipid Transfer Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection
chemical_list: D002308:Cardiolipins; D017931:DNA Primers; D008563:Membrane Lipids; C493424:PLSCR3 protein, human; D049294:Phospholipid Transfer Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051745:Protein Kinase C-delta; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases