Diverse Scaffolds Facilitate NLRP3 Clustering and Inflammasome Formation in Response to Perturbations in Cell Homeostasis

A central component of innate immunity, the NLRP3 inflammasome is a multiprotein complex formed in response to a chemically and morphologically diverse spectrum of stimuli. Despite extensive investigation, no single ligand or signal has emerged to account for this breadth of activation. Here, we review the landscape of NLRP3 activation across subcellular compartments and examine how this process is shaped by a network of interacting partners. Recent studies suggest that NLRP3 responds to cellular perturbations, such as changes in lipid membrane composition, protein localization, or organelle function. We propose that distinct upstream cues converge to generate diverse molecular scaffolds that recruit NLRP3. The NLRP3‐scaffold interactions promote NLRP3 clustering, destabilize its autoinhibited conformation, and drive assembly of the inflammasome. NLRP3 is thus an adaptable sensor, equipped with versatile molecular interactions that allow it to integrate multiple danger signals into inflammasome activation.