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Guanylate binding proteins promote caspase-11–dependent pyroptosis in response to cytoplasmic LPS
- Pilla, Danielle M., Hagar, Jon A., Haldar, Arun K., Mason, Ashley K., Degrandi, Daniel, Pfeffer, Klaus, Ernst, Robert K., Yamamoto, Masahiro, Miao, Edward A., Coers, Jörn
- Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.16 pp. 6046-6051
- Escherichia coli, Legionella pneumophila, Salmonella, binding proteins, caspase-11, chromosomes, cytosol, immune response, macrophages, mice, microbial detection, mutants, pathogens
- IFN receptor signaling induces cell-autonomous immunity to infections with intracellular bacterial pathogens. Here, we demonstrate that IFN-inducible guanylate binding protein (Gbp) proteins stimulate caspase-11–dependent, cell-autonomous immunity in response to cytoplasmic LPS. Caspase-11–dependent pyroptosis is triggered in IFN-activated macrophages infected with the Gram-negative bacterial pathogen Legionella pneumophila. The rapid induction of pyroptosis in IFN-activated macrophages required a cluster of IFN-inducible Gbp proteins encoded on mouse chromosome 3 (Gbp ᶜʰʳ³). Induction of pyroptosis in naive macrophages by infections with the cytosol-invading Δ sdhA L. pneumophila mutant was similarly dependent on Gbp ᶜʰʳ³, suggesting that these Gbp proteins play a role in the detection of bacteria accessing the cytosol. Cytoplasmic LPS derived from Salmonella ssp. or Escherichia coli has recently been shown to trigger caspase-11 activation and pyroptosis, but the cytoplasmic sensor for LPS and components of the caspase-11 inflammasome are not yet defined. We found that the induction of caspase-11–dependent pyroptosis by cytoplasmic L. pneumophila -derived LPS required Gbp ᶜʰʳ³ proteins. Similarly, pyroptosis induced by cytoplasmic LPS isolated from Salmonella was diminished in Gbp ᶜʰʳ³-deficient macrophages. These data suggest a role for Gbp ᶜʰʳ³ proteins in the detection of cytoplasmic LPS and the activation of the noncanonical inflammasome.