Assembly and Activation of the NLR Family in Innate Immune Regulation and Cell Death

The nucleotide-binding oligomerization domain (NOD)-like receptor, or nucleotide-binding (NBD) leucine-rich repeat receptor (NLR) family, comprises a group of evolutionarily conserved intracellular pattern recognition receptors (PRRs) that are critical for innate immunity and broader physiological and pathological processes. In humans, the NLR family plays a central role in inflammatory cell death, known as pyroptosis, by acting as intracellular sensors that trigger the assembly of inflammasomes. These inflammasomes eventually lead to the activation of inflammatory caspases and the cleavage of key substrates, such as pro–IL-1β, pro–IL-18, and gasdermin D (GSDMD), which oligomerizes to form pores in the plasma membrane. Recent structural studies have illuminated the molecular transitions that underpin inflammasome activation, revealing how these complexes shift from autoinhibited states to dynamic supramolecular signaling platforms. Plant and bacterial NLRs do not form inflammasomes upon activation, but they assemble into resistosomes or similar supramolecular platforms, respectively. This chapter synthesizes advances in our understanding of the structural architecture, assembly principles, and regulatory mechanisms of typical supramolecular complex platforms that mediate innate immunity and cell death. By linking molecular insights to functional outcomes, we highlight their roles in innate immune regulation and cell death.