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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.