Open AccessDiscovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes
Author(s) -
Erinna F. Lee,
Oliver Clarke,
Marco Evangelista,
Zhiping Feng,
Terence P. Speed,
Elissaveta B. Tchoubrieva,
Andreas Strasser,
Bernd H. Kalinna,
Peter M. Colman,
W. Douglas Fairlie
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1100652108
Subject(s) - biology , apoptosis , programmed cell death , drug discovery , microbiology and biotechnology , mitochondrion , schistosomiasis , schistosoma , schistosoma mansoni , cancer cell , schistosoma japonicum , cell , computational biology , biochemistry , cancer , genetics , immunology , helminths
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 inSchistosoma japonicum andS. 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.