Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.
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 ΔsdhA 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.
Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710.
Danielle M
DM
Pilla
Jon A
JA
Hagar
Arun K
AK
Haldar
Ashley K
AK
Mason
Daniel
D
Degrandi
Klaus
K
Pfeffer
Robert K
RK
Ernst
Masahiro
M
Yamamoto
Edward A
EA
Miao
Jörn
J
Coers
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D016952:Legionella pneumophila / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D007877:Legionnaires' Disease / Q000382:microbiology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000502:physiology
C096000:Ifi1 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D019204:GTP-Binding Proteins
Nos2; cell death; immunity-related GTPases; interferon