Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase

Mol Cell. 2004 Jun 18;14(6):801-11. doi: 10.1016/j.molcel.2004.05.018.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspases / metabolism
  • Caspases / pharmacology
  • Cell Line, Tumor
  • DNA, Complementary / metabolism
  • HeLa Cells
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mutation
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Ubiquitin-Conjugating Enzymes / analysis
  • Ubiquitin-Conjugating Enzymes / metabolism*
  • Ubiquitin-Protein Ligases / analysis
  • Ubiquitin-Protein Ligases / metabolism*
  • trans-Golgi Network / chemistry


  • BIRC6 protein, mouse
  • DNA, Complementary
  • Inhibitor of Apoptosis Proteins
  • Neoplasm Proteins
  • Recombinant Fusion Proteins
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • Caspases