Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase.
Apoptotic cell death and survival is controlled by pro- and antiapoptotic proteins. Because these proteins act on each other, cell fate is dictated by the relative activity of pro- versus antiapoptotic proteins. Here we report that BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi network, protects cells against apoptosis and functions as an inhibitor of apoptosis (IAP). By using wild-type and mutant forms we show that BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. Upon apoptosis induction, BRUCE is antagonized by three mechanisms: first, through binding to Smac; second, by the protease HtrA2; and third, by caspase-mediated cleavage. In addition to its IAP activity BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase with Smac being a substrate. Our work suggests that, owing to its two activities and its localization, BRUCE may function as a specialized regulator of cell death pathways.
Bartke
Till
T
Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Pohl
Christian
C
Pyrowolakis
George
G
Jentsch
Stefan
S
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044763:Ubiquitin-Conjugating Enzymes / Q000032:analysis / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000378:metabolism*; D021601:trans-Golgi Network / Q000737:chemistry
C490597:BIRC6 protein, mouse; D018076:DNA, Complementary; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D020169:Caspases