Thirty years of reaper: lessons learned from programmed cell death in Drosophila

April 2024 marked the 30-year anniversary of the publication of reaper , the first description of a Drosophila cell death gene. This discovery established the foundation for modern apoptosis research in Drosophila and fundamentally reshaped studies on programmed cell death (PCD). This review provides a historical and mechanistic overview of apoptosis research in Drosophila , with a particular emphasis on the discovery and legacy of reaper . Rather than providing a comprehensive review of the entire field, this article emphasizes some of the main lessons learned from Drosophila cell death research and their general impact. One of the first lessons was that reaper is transcriptionally activated by many different death-inducing signals, suggesting that apoptosis is a transcriptionally regulated, developmentally patterned process. Mechanistically, reaper and its neighboring genes head involution defective (hid) , grim , and sickle, collectively referred to as RHG genes, induce apoptosis by neutralizing the anti-apoptotic Drosophila Inhibitor of Apoptosis-1 (DIAP1) protein. DIAP1 is required to prevent unwanted caspase activation and apoptosis in virtually all somatic cells. RHG proteins de-repress caspases by inducing the self-conjugation and degradation of this E3-ligase protein. This mechanism provided a conceptual bridge to mammalian IAP-antagonists such as Smac/DIABLO and ARTS, which were discovered 6 years later. The RHG proteins introduced a fundamental principle in cell death regulation: that apoptosis in higher animals can be triggered by precisely controlled expression of IAP antagonists, rather than activation of caspases alone. Over 3 decades, Drosophila has proven indispensable in elucidating caspase regulation in vivo , transcriptional control of cell death, the role of apoptosis in developmental and tissue morphogenesis, the hormonal regulation of apoptosis, ubiquitin-proteasome-mediated protein degradation in cell death, apoptosis-induced proliferation, and non-apoptotic cell death pathways, including autophagic, necrotic, and inflammatory forms of regulated cell death. Due to its genetic and anatomical accessibility, Drosophila continues to drive conceptual advances with relevance to cancer, neurodegeneration, immunity, and regeneration.