IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes.
The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the pro-inflammatory cytokines IL-1β and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria. IRGB10 directly targeted cytoplasmic bacteria through a mechanism requiring guanylate-binding proteins. Localization of IRGB10 to the bacterial cell membrane compromised bacterial structural integrity and mediated cytosolic release of ligands for recognition by inflammasome sensors. Overall, our results reveal IRGB10 as part of a conserved signaling hub at the interface between cell-autonomous immunity and innate immune sensing pathways.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Si Ming
SM
Man
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Rajendra
R
Karki
Department of Immunoparasitology, Research Institute for Microbial Diseases, Laboratory of Immunoparasitology, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Miwa
M
Sasai
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
David E
DE
Place
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Sannula
S
Kesavardhana
Department of Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Jamshid
J
Temirov
Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Sharon
S
Frase
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Qifan
Q
Zhu
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
R K Subbarao
RKS
Malireddi
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Teneema
T
Kuriakose
Department of Cellular Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Jennifer L
JL
Peters
Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Geoffrey
G
Neale
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Scott A
SA
Brown
Department of Immunoparasitology, Research Institute for Microbial Diseases, Laboratory of Immunoparasitology, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Masahiro
M
Yamamoto
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org.
Thirumala-Devi
TD
Kanneganti
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D003600:Cytosol / Q000276:immunology / Q000382:microbiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005603:Francisella / Q000276:immunology*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D016905:Gram-Negative Bacterial Infections / Q000276:immunology* / Q000382:microbiology; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007111:Immunity, Cellular; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D008024:Ligands; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020558:GTP Phosphohydrolases; C515445:Irgb10 protein, mouse
GBP2; GBP5; GBPs; LPS; caspase-1; cell-autonomous immunity; immunity-related GTPases; innate immunity; interferons; non-canonical inflammasome
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