Molecular mechanisms of NLR proteins in inflammasome activation.

Nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) are central mediators of inflammasome signaling, activating caspase-1 to drive pyroptotic cell death and pro-inflammatory responses. Although NLR activation is generally thought to involve conformational rearrangements that oligomerize their N- or C-terminal death domains to nucleate ASC or pro-caspase-1 oligomerization, the molecular mechanisms that enable these transitions vary substantially among family members. Here, we highlight recent structural advances that reveal how distinct NLRs are activated and assemble into higher-order signaling platforms, providing mechanistic insights into the diverse activation mechanisms that converge on a common inflammatory outcome.