The NLRs are a family of pattern-recognition receptors that sense intracellular pathogens. NLRs have leucine-rich repeat (LRR) regions and nucleotide-binding domains that regulate the formation and function of inflammasomes. In Molecular Cell, Vance and colleagues reveal the molecular basis of ligand recognition by a class of NLRs that associate with NLRC4 to form inflammasomes. Analysis of a library of chimeric NLRs with swapped NAIP2, NAIP5 and NAIP6 domains reveals that α-helical domains located adjacent to the nucleotide-binding domains are responsible for specific ligand recognition, contrary to expectation that flexible LRR regions mediate such recognition. Comparative genetic analysis suggests this α-helical region has undergone positive selection to diversify. Although the LRR regions might contribute to the recognition of ligand by other NLRs, this domain seems to mediate only autoinhibition to prevent spurious inflammasome activation by NAIPs.

Mol. Cell 54, 17–29 (10 April 2014)