Broad detection of bacterial type III secretion system and flagellin proteins by the human NAIP/NLRC4 inflammasome

Significance Inflammasomes are cytosolic multiprotein complexes that initiate innate immune responses to microbial infection. Inflammasome specificity is determined by cytosolic innate immune sensors, including nucleotide-binding domain, leucine-rich repeat-containing family, apoptosis inhibitory proteins (NAIPs). In mice, which encode seven different NAIPs, individual NAIPs recognize specific components of the structurally related bacterial type III secretion system (T3SS) and flagellar apparatus. Humans encode a single functional NAIP, raising the question of whether human NAIP recognizes the same repertoire of bacterial ligands. Here, we find that, in contrast to the ligand specificity exhibited by the murine NAIPs, the single human NAIP broadly detects multiple T3SS and flagellin proteins. These findings provide a basis for understanding the mechanisms underlying human-specific innate immune responses against bacterial infection.