Drosophila Bruce can potently suppress Rpr- and Grim-dependent but not Hid-dependent cell death.
Bruce is a large protein (530 kDa) that contains an N-terminal baculovirus IAP repeat (BIR) and a C-terminal ubiquitin conjugation domain (E2). BRUCE upregulation occurs in some cancers and contributes to the resistance of these cells to DNA-damaging chemotherapeutic drugs. However, it is still unknown whether Bruce inhibits apoptosis directly or instead plays some other more indirect role in mediating chemoresistance, perhaps by promoting drug export, decreasing the efficacy of DNA damage-dependent cell death signaling, or by promoting DNA repair. Here, we demonstrate, using gain-of-function and deletion alleles, that Drosophila Bruce (dBruce) can potently inhibit cell death induced by the essential Drosophila cell death activators Reaper (Rpr) and Grim but not Head involution defective (Hid). The dBruce BIR domain is not sufficient for this activity, and the E2 domain is likely required. dBruce does not promote Rpr or Grim degradation directly, but its antiapoptotic actions do require that their N termini, required for interaction with DIAP1 BIR2, be intact. dBruce does not block the activity of the apical cell death caspase Dronc or the proapoptotic Bcl-2 family member Debcl/Drob-1/dBorg-1/Dbok. Together, these results argue that dBruce can regulate cell death at a novel point.
Division of Biology, MC 156-29, California Institute of Technology, 1200 East California Boulevard, Pasadena 91125, USA.
Stephanie Y
SY
Vernooy
Vivian
V
Chow
Julius
J
Su
Koen
K
Verbrugghe
Jennifer
J
Yang
Susannah
S
Cole
Michael R
MR
Olson
Bruce A
BA
Hay
D000818:Animals; D017209:Apoptosis; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D051034:Inhibitor of Apoptosis Proteins; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
C401541:BIRC6 protein, human; C470733:Bruce protein, Drosophila; D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D009479:Neuropeptides; D025801:Ubiquitin; C108881:grim protein, Drosophila; C086973:rpr protein, Drosophila