title: Drosophila IAP antagonists form multimeric complexes to promote cell death.
abstract: Apoptosis is a specific form of cell death that is important for normal development and tissue homeostasis. Caspases are critical executioners of apoptosis, and living cells prevent their inappropriate activation through inhibitor of apoptosis proteins (IAPs). In Drosophila, caspase activation depends on the IAP antagonists, Reaper (Rpr), Head involution defective (Hid), and Grim. These proteins share a common motif to bind Drosophila IAP1 (DIAP1) and have partially redundant functions. We now show that IAP antagonists physically interact with each other. Rpr is able to self-associate and also binds to Hid and Grim. We have defined the domain involved in self-association and demonstrate that it is critical for cell-killing activity in vivo. In addition, we show that Rpr requires Hid for recruitment to the mitochondrial membrane and for efficient induction of cell death in vivo. Both targeting of Rpr to mitochondria and forced dimerization strongly promotes apoptosis. Our results reveal the functional importance of a previously unrecognized multimeric IAP antagonist complex for the induction of apoptosis.
authors.affiliation: Howard Hughes Medical Institute, Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Cristinel
authors.initials: C
authors.lastname: Sandu
authors.forename: Hyung Don
authors.initials: HD
authors.lastname: Ryoo
authors.forename: Hermann
authors.initials: H
authors.lastname: Steller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000378:metabolism*; D005123:Eye / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D021381:Protein Transport; D054875:Ubiquitination
chemical_list: D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D046912:Multiprotein Complexes