IRGB10 Liberates Bacterial Ligands for Sensing by the AIM2 and Caspase-11-NLRP3 Inflammasomes
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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.
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Type I IFN and IFNG contribute to pyroptosis by promoting expression of guanylate-binding proteins and IRGB10, which increase cytosolic LPS levels by mediating lysis of vacuoles containing Gram-negative bacteria.
“(3) the expression of guanylate-binding proteins and an IFN-inducible GTPase commonly known as IRGB10 (official name Gm12250), which increase cytosolic LPS levels by mediating the lysis of vacuoles containing Gram-negative bacteria [646–648].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [648]
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Role of AIM2 inflammasome in inflammatory diseases, cancer and infection
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Self-citationHuman GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria
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Mechanisms governing inflammasome activation, assembly and pyroptosis induction
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Self-citationPANoptosis in microbial infection
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Inflammasome Priming in Sterile Inflammatory Disease
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DNA Sensing in the Innate Immune Response
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Self-citationUbiquitination and degradation of GBPs by a Shigella effector to suppress host defence
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Molecular mechanisms of inflammasome signaling
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Self-citationDNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer
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Cell biology of inflammasome activation
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Self-citationInflammasome Activation by Bacterial Outer Membrane Vesicles Requires Guanylate Binding Proteins
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Self-citationThe Signaling Pathways Regulating NLRP3 Inflammasome Activation
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Differential roles of caspase-1 and caspase-11 in infection and inflammation
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TLRs/NLRs: Shaping the landscape of host immunity
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Inflammasomes and the fine line between defense and disease
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Self-citationPyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target
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Innate, adaptive, and cell-autonomous immunity against Toxoplasma gondii infection
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Self-citationIntracellular Lipopolysaccharide Sensing as a Potential Therapeutic Target for Sepsis
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Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β
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Self-citationOuter Membrane Lipid Secretion and the Innate Immune Response to Gram-Negative Bacteria
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Intracellular innate immune receptors: Life inside the cell
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Self-citationFatty acid activates NLRP3 inflammasomes in mouse Kupffer cells through mitochondrial DNA release
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Innate Sensors Trigger Regulated Cell Death to Combat Intracellular Infection
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Targeting NLRP3 Inflammasome Activation in Severe Asthma
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Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation
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Self-citationSignaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases
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Self-citationThe role of lysosome in regulated necrosis
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Self-citationExposing Toxoplasma gondii hiding inside the vacuole: a role for GBPs, autophagy and host cell death
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Self-citationAdvances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators
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Self-citationThe advances in pyroptosis initiated by inflammasome in inflammatory and immune diseases
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Fantastic voyage: The journey of NLRP3 inflammasome activation
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Self-citationBacterial outer membrane vesicles and host cell death signaling
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Self-citationInflammasomes: Mechanisms of Action and Involvement in Human Diseases
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Self-citationDifferential role of the NLRP 3 inflammasome in infection and tumorigenesis
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Self-citationRole of inflammasomes/pyroptosis and PANoptosis during fungal infection
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Self-citation
- Authors
- Man, S. M., Karki, R., Sasai, M., Place, D. E., Kesavardhana, S., Temirov, J., Frase, S., Zhu, Q., Malireddi, R. K. S., Kuriakose, T., Peters, J. L., Neale, G., Brown, S. A., Yamamoto, M., & Kanneganti, T.-D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Corresponding author
- Kanneganti, Thirumala-Devi
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 167
- Issue
- 2
- Pages
- 382-396.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5074697
- OpenAlex
- W2524431814
- Cited by
- 312
- References
- 57
- Citations by year
- 2026: 12 · 2025: 35 · 2024: 18 · 2023: 28 · 2022: 32 · 2021: 30 · 2020: 49 · 2019: 37 · 2018: 31 · 2017: 37 · 2016: 2
- FWCI
- 18.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Cancer Institute (R01CA163507, P30CA021765)
- National Institute of Allergy and Infectious Diseases (R01AI101935, R37AI101935, R01AI124346)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056296)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- AIM2 inflammasome, caspase-11, NLRP3 inflammasome, Francisella novicida, Gram-negative bacteria, guanylate-binding proteins, plasma membrane targeting, DNA sensing, pyroptosis, IL-1β, IL-18, cell-autonomous immunity, innate immune recognition
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, B-Lymphocytes, Cytosol, DNA-Binding Proteins, Francisella, Immunity, Cellular, Immunity, Innate, Ligands, Mice, Mutant Strains, T-Lymphocytes, Gram-Negative Bacterial Infections, Caspases, GTP Phosphohydrolases, Myeloid Cells, Mice, Caspases, Initiator, Host-Pathogen Interactions, Inflammasomes
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