title: Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.
abstract: Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
authors: Erinna F
authors: EF
authors: Lee
authors: Oliver B
authors: OB
authors: Clarke
authors: Marco
authors: M
authors: Evangelista
authors: Zhiping
authors: Z
authors: Feng
authors: Terence P
authors: TP
authors: Speed
authors: Elissaveta B
authors: EB
authors: Tchoubrieva
authors: Andreas
authors: A
authors: Strasser
authors: Bernd H
authors: BH
authors: Kalinna
authors: Peter M
authors: PM
authors: Colman
authors: W Douglas
authors: WD
authors: Fairlie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015801:Helminth Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012549:Schistosoma japonicum / Q000235:genetics / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000235:genetics / Q000378:metabolism*; D012554:Schistosomiasis japonica / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D015801:Helminth Proteins; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides