The IAP family member BRUCE/BIRC6: an emerging new player in balancing life and death

Cell survival and death are the fundamental biological processes of life that involve both intracellular and extracellular dynamic events. How cells balance survival and death determines cell fate, and this question has attracted extensive research interest for decades yet remains largely unresolved. This review focuses on BRUCE, the only essential inhibitor-of-apoptosis (IAP) protein for survival. Based on recent structural discoveries regarding the autophagy-apoptosis switch, we provide novel mechanistic insights into this long-standing scientific question. BRUCE possesses a distinctive structure: its C-terminal UBC domain confers Ub conjugase (E2) and Ub-protein ligase (E3) activities, while its N-terminal region contains a baculoviral IAP repeat (BIR) domain. Benefiting from such distinctive structural properties. BRUCE centrally governs cell fate by modulating the transition from autophagy to apoptosis and maintaining genomic stability. At the organismal level, BRUCE sustains the homeostasis of reproductive and developmental processes by either inhibiting apoptosis or mediating substrate degradation. Aberrant BRUCE upregulation is widely implicated in diverse pathologies, including neurodevelopmental disorders and multiple malignancies. Nevertheless, research focusing on the targeted inhibition of BRUCE remains largely underexplored. A better understanding of the structural features and functional mechanisms of BRUCE will help elucidate how it exerts its pathogenic effects via regulation of cell survival and death. Such insights will lay a solid foundation for the future discovery and therapeutic application of specific BRUCE-targeted inhibitors. Outlooks and perspectives on the associated challenges are provided as well.