title: The IAP-antagonist ARTS initiates caspase activation upstream of cytochrome C and SMAC/Diablo.
abstract: ARTS (Sept4_i2) is a pro-apoptotic tumor suppressor protein that functions as an antagonist of X-linked IAP (XIAP) to promote apoptosis. It is generally thought that mitochondrial outer membrane permeabilization (MOMP) occurs before activation of caspases and is required for it. Here, we show that ARTS initiates caspase activation upstream of MOMP. In living cells, ARTS is localized to the mitochondrial outer membrane. In response to apoptotic signals, ARTS translocates rapidly to the cytosol in a caspase-independent manner, where it binds XIAP and promotes caspase activation. This translocation precedes the release of cytochrome C and SMAC/Diablo, and ARTS function is required for the normal timing of MOMP. We also show that ARTS-induced caspase activation leads to cleavage of the pro-apoptotic Bcl-2 family protein Bid, known to promote MOMP. We propose that translocation of ARTS initiates a first wave of caspase activation that can promote MOMP. This leads to the subsequent release of additional mitochondrial factors, including cytochrome C and SMAC/Diablo, which then amplifies the caspase cascade and causes apoptosis.
authors.affiliation: Department of Biology, Faculty of Natural Sciences, Cell Death Research Laboratory, University of Haifa, Multi-Purpose Building, Mount Carmel, Haifa 31905, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Edison
authors.forename: D
authors.initials: D
authors.lastname: Zuri
authors.forename: I
authors.initials: I
authors.lastname: Maniv
authors.forename: B
authors.initials: B
authors.lastname: Bornstein
authors.forename: T
authors.initials: T
authors.lastname: Lev
authors.forename: Y
authors.initials: Y
authors.lastname: Gottfried
authors.forename: S
authors.initials: S
authors.lastname: Kemeny
authors.forename: M
authors.initials: M
authors.lastname: Garcia-Fernandez
authors.forename: J
authors.initials: J
authors.lastname: Kagan
authors.forename: S
authors.initials: S
authors.lastname: Larisch
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D019556:COS Cells; D053453:Caspase 9 / Q000378:metabolism*; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008954:Models, Biological; D021381:Protein Transport; D058112:Septins / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D045304:Cytochromes c; D053453:Caspase 9; C492027:SEPTIN4 protein, human; D058112:Septins