LPS-induced structural reorganization and polymerization drive noncanonical inflammasome activation

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…

• NI
  National Institutes of Health

  Awards: R01AI158435, S10 grant S10OD028574., R01AI119015, RM1GM149374