Comparative insights into the apoptosome, inflammasomes and PIDDosome

Caspase activation platforms such as the apoptosome, inflammasome and PIDDosome are central to cellular responses to stress, coordinating inflammation, cell death and cell differentiation. Although each of these complexes has been extensively studied in isolation, a comparative understanding of their structural and functional principles is lacking. Here we provide an integrated review of the architecture, activation mechanisms and signalling outputs of these supramolecular signalling platforms. All three of these platforms share a broadly conserved domain architecture and promote proximity-induced caspase activation, but they differ in their subcellular localization and upstream triggers. Furthermore, we explore differences in their downstream effectors and roles in immune signalling, cell cycle regulation and tissue homeostasis. Germline mutations in humans affecting these complexes are linked to cancer predisposition, immune dysregulation and neurodevelopmental disorders, respectively. Finally, we discuss therapeutic opportunities and unresolved questions, aiming to stimulate cross-disciplinary research and translational applications.