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.
Mesh Terms:
Animals, Apoptosis, Caspases, Cell Line, Tumor, DNA, Complementary, HeLa Cells, Humans, Inhibitor of Apoptosis Proteins, Mice, Mutation, Neoplasm Proteins, Recombinant Fusion Proteins, Signal Transduction, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, trans-Golgi Network
Animals, Apoptosis, Caspases, Cell Line, Tumor, DNA, Complementary, HeLa Cells, Humans, Inhibitor of Apoptosis Proteins, Mice, Mutation, Neoplasm Proteins, Recombinant Fusion Proteins, Signal Transduction, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, trans-Golgi Network
Mol. Cell
Date: Jun. 18, 2004
PubMed ID: 15200957
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