When folding CARDs wins the game: molecular snapshots of lipopolysaccharide sensing by the non-canonical inflammasome.

Inflammatory caspases play essential roles in regulating IL-1 cytokine processing and secretion, as well as in inducing pyroptosis as part of the innate immune response to pathogens and other noxious stimuli. While the activation of caspase-1 is controlled by dedicated pattern recognition receptors, human caspase-4 and caspase-5, and murine caspase-11 function themselves as direct sensors for lipopolysaccharide (LPS), the immunostimulatory component of the Gram-negative bacterial outer membrane. These caspases bind LPS through their N-terminal caspase recruitment domain (CARD), which triggers their oligomerization and activation. Recent studies have provided new insights into the molecular basis of LPS recognition by the caspase-4/11 CARD, including its interactions with LPS and other lipid ligands, the evolutionary origins of inflammatory caspases, the structural organization of LPS-caspase complexes, and the regulatory mechanisms that govern CARD-ligand association. In this review, we summarize these advances and discuss their implications for inflammatory caspase activation and innate immune signaling.