Baculoviral IAP repeat-containing protein 6 (BIRC6)

Baculoviral IAP repeat-containing protein 6 (BIRC6) is a gigantic multi-domain protein that acts as both an E2 ubiquitin-conjugating enzyme and E3 ubiquitin ligase, and is a unique member of the inhibitor of apoptosis proteins (IAPs) family[1][2][3][5]. BIRC6 prevents programmed cell death (apoptosis) primarily by mediating the ubiquitination and proteasomal degradation of pro-apoptotic proteins such as SMAC/DIABLO and caspase-9, and it directly inhibits executioner caspases, thereby ensuring cell survival[3][4][5][7]. BIRC6 is also a suppressor of autophagy, limiting autophagosome formation through regulation of LC3 levels[5]. Highly expressed in a variety of cancers, BIRC6 contributes to tumor growth, chemoresistance, enhanced stemness, and activation of oncogenic pathways such as β-catenin signaling[6]. Its essential role in both apoptosis and autophagy, along with its unique structural features (horseshoe-shaped dimer with a large central cavity for substrate binding), make BIRC6 a promising therapeutic target in cancer, though safety concerns and lack of clinically approved direct inhibitors remain challenges[1][2][7].

Other names

ApollonBRUCEDual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6KIAA1289Baculoviral IAP repeat-containing 6BIR repeat-containing ubiquitin-conjugating enzymeRING-type E3 ubiquitin transferase BIRC6Ubiquitin-conjugating BIR domain enzyme apollon

Ubiquitylation and proteasomal degradation of caspases and SMAC/DIABLO to suppress apoptosis[4][5]; Ubiquitin-mediated regulation of autophagy-related proteins (e.g., LC3B); Modulation of β-catenin pathway via ubiquitination and degradation of Axin[6]; Some strategies involve restoring apoptosis in cancer cells by antagonizing BIRC6 with SMAC or SMAC mimetics[2][7]