LPS-induced structural reorganization and polymerization drive noncanonical inflammasome activation.

ABSTRACT: The noncanonical inflammasome, mediated by murine caspase-11 and its human orthologs caspase-4 and caspase-5, detects intracellular lipopolysaccharide (LPS) and triggers pyroptotic cell death. Upon LPS binding through their amino-terminal caspase activation and recruitment domains (CARDs), these inflammatory caspases oligomerize and activate. However, how LPS binding drives caspase-4/11 activation remains unclear. Here, we show that caspase-4/11 CARDs are intrinsically unstructured in their resting state and adopt an α-helical conformation upon LPS engagement. This structural rearrangement promotes CARD oligomerization, with electron-capture charge reduction-coupled native mass spectrometry and other techniques illustrating that hexa-acylated LPS induces the formation of large oligomers co

SUBMITTER: Wang C 

PROVIDER: S-EPMC12757046 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature