Supramolecular Assemblies Drive Activation of Inflammasomes.

Inflammasomes are large cytosolic protein complexes that detect and respond to pathogenic and endogenous danger signals, triggering critical innate immune defenses. This chapter outlines the structural and mechanistic features of canonical inflammasomes, focusing on NLRP1, NLRP3, NAIP-NLRC4, NLRP6, and AIM2. Canonical inflammasomes often comprise a sensor protein (e.g., an NLR or AIM2), the adaptor ASC, and pro-caspase-1, which are assembled upon ligand binding. NLR sensors detect diverse signals, ranging from bacterial toxins and lipopolysaccharides to crystals and ATP, while AIM2 recognizes cytosolic double-stranded DNA. Once activated, these inflammasomes facilitate caspase-1-dependent maturation of IL-1β and IL-18, as well as cleavage of gasdermin D, culminating in pyroptotic cell death and pro-inflammatory cytokine release. Structural insights reveal that inflammasome activation transitions from an autoinhibited state to filamentous or ring-shaped supramolecular assemblies. Despite ligand diversity and varying activation pathways, inflammasomes share unifying principles in their oligomerization-driven activation. Elucidating these mechanisms advances our understanding of how cells mount rapid, robust immune responses and paves the way for developing therapeutic interventions in inflammatory and infectious diseases.