title: Effectors of alcohol-induced cell killing in Drosophila.
abstract: Heavy alcohol consumption provokes an array of degenerative pathologies but the signals that couple alcohol exposure to regulated forms of cell death are poorly understood. Using Drosophila as a model, we genetically establish that the severity of ethanol challenge dictates the type of death that occurs. In contrast to responses seen under acute exposure, cytotoxic responses to milder challenges required gene encoding components of the apoptosome, Dronc and Dark. We conducted a genome-wide RNAi screen to capture targets that specifically mediate ethanol-induced cell death. One effector, Drat, encodes a novel protein that contains an ADH domain but lacks essential residues in the catalytic site. In cultured cells and neurons in vivo, depletion of Drat conferred protection from alcohol-induced apoptosis. Adults mutated for Drat showed both improved survival and enhanced propensities toward sedation after alcohol challenge. Together, these findings highlight novel effectors that support regulated cell death incited by alcohol stress in vitro and in vivo.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Tu
authors.forename: F
authors.initials: F
authors.lastname: Akdemir
authors.forename: S K
authors.initials: SK
authors.lastname: Chew
authors.forename: A
authors.initials: A
authors.lastname: Rothenfluh
authors.forename: J M
authors.initials: JM
authors.lastname: Abrams
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053478:Apoptosomes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004330:Drosophila / Q000187:drug effects* / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference
chemical_list: D053478:Apoptosomes; D029721:Drosophila Proteins; C400550:dark protein, Drosophila; D000431:Ethanol; D036002:ADP Ribose Transferases; C057637:dinitrogenase reductase ADP-ribosyltransferase; D020169:Caspases; C118731:dronc protein, Drosophila