Caspase-11 Cleaves Gasdermin D for Non-Canonical Inflammasome Signalling

Nature. 2015 Oct 29;526(7575):666-71. doi: 10.1038/nature15541. Epub 2015 Sep 16.

Abstract

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1β processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1β secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Caspases / metabolism*
  • Cell Line
  • Female
  • Gram-Negative Bacteria / immunology
  • Humans
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mice
  • Mutation / genetics
  • Necrosis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Protein Processing, Post-Translational / drug effects
  • Sepsis / microbiology
  • Signal Transduction* / genetics
  • Survival Analysis

Substances

  • Apoptosis Regulatory Proteins
  • GSDMD protein, human
  • Gsdmd protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • Neoplasm Proteins
  • Casp4 protein, mouse
  • Caspases