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Nature Cell Biology 6, 849–860 (1 September 2004) | doi:10.1038/ncb1159

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

Yanyan Hao , Keiko Sekine , Atsushi Kawabata , Hitoshi Nakamura , Toshiyasu Ishioka , Hirokazu Ohata , Ryohei Katayama , Chizuko Hashimoto , Xiaodong Zhang , Tetsuo Noda , Takashi Tsuruo & Mikihiko Naito

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.