Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function

Nat Cell Biol. 2004 Sep;6(9):849-60. doi: 10.1038/ncb1159. Epub 2004 Aug 8.

Abstract

Apollon (also known as BRUCE or BIRC6) is a large protein containing baculoviral-IAP-repeat (BIR) and ubiquitin-conjugating enzyme (UBC) domains at the amino- and carboxy termini, respectively. Apollon inhibits apoptosis, but its molecular and physiological function remains unclear. Here we report that Apollon binds to, ubiquitinates and facilitates proteasomal degradation of SMAC and caspase-9, which both contain IAP-binding motifs. Targeted disruption of Apollon in mice caused embryonic and neonatal lethality. Notably, SMAC induced apoptosis in Apollon-deficient cells, but not in Apollon-expressing cells. Furthermore, the IAP-binding motif of SMAC was required to induce apoptosis in Apollon-deficient cells. These results suggest that Apollon has an essential function in preventing SMAC-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / metabolism*
  • Caspase 9
  • Caspases / metabolism*
  • Cysteine Endopeptidases / metabolism
  • Fetal Death
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Protective Agents
  • U937 Cells
  • Ubiquitin-Conjugating Enzymes / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BIRC6 protein, human
  • BIRC6 protein, mouse
  • Carrier Proteins
  • DIABLO protein, human
  • Diablo protein, mouse
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Neoplasm Proteins
  • Protective Agents
  • Ubiquitin-Conjugating Enzymes
  • CASP9 protein, human
  • Casp9 protein, mouse
  • Caspase 9
  • Caspases
  • Cysteine Endopeptidases