Inflammatory caspases are innate immune receptors for intracellular LPS

Nature. 2014 Oct 9;514(7521):187-92. doi: 10.1038/nature13683. Epub 2014 Aug 6.


The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by human caspase-4 that could functionally complement murine caspase-11. Human caspase-4 and the mouse homologue caspase-11 (hereafter referred to as caspase-4/11) and also human caspase-5, directly bound to LPS and lipid A with high specificity and affinity. LPS associated with endogenous caspase-11 in pyroptotic cells. Insect-cell purified caspase-4/11 underwent oligomerization upon LPS binding, resulting in activation of the caspases. Underacylated lipid IVa and lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) could bind to caspase-4/11 but failed to induce their oligomerization and activation. LPS binding was mediated by the CARD domain of the caspase. Binding-deficient CARD-domain point mutants did not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections. The function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases / chemistry
  • Caspases / genetics
  • Caspases / immunology
  • Caspases / metabolism*
  • Caspases, Initiator / chemistry
  • Caspases, Initiator / genetics
  • Caspases, Initiator / immunology
  • Caspases, Initiator / metabolism*
  • Cell Death / drug effects
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Genetic Complementation Test
  • Humans
  • Immunity, Innate*
  • Inflammation / enzymology
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Lipid A / metabolism
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism*
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Necrosis / chemically induced
  • Protein Binding
  • Protein Multimerization / drug effects
  • Protein Multimerization / genetics
  • Rhodobacter sphaeroides / chemistry
  • Rhodobacter sphaeroides / immunology
  • Substrate Specificity
  • Surface Plasmon Resonance


  • Lipid A
  • Lipopolysaccharides
  • Mutant Proteins
  • CASP4 protein, human
  • CASP5 protein, human
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator