The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection
Open accessAbstract
Inflammasomes are critical for mounting host defense against pathogens. The molecular mechanisms that control activation of the AIM2 inflammasome in response to different cytosolic pathogens remain unclear. Here we found that the transcription factor IRF1 was required for activation of the AIM2 inflammasome during infection with the Francisella tularensis subspecies novicida (F. novicida), whereas engagement of the AIM2 inflammasome by mouse cytomegalovirus (MCMV) or transfected double-stranded DNA did not require IRF1. Infection of F. novicida detected by the DNA sensor cGAS and its adaptor STING induced type I interferon-dependent expression of IRF1, which drove the expression of guanylate-binding proteins (GBPs); this led to intracellular killing of bacteria and DNA release. Our results reveal a specific requirement for IRF1 and GBPs in the liberation of DNA for sensing by AIM2 depending on the pathogen encountered by the cell.
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Type I IFN and IFNG contribute to pyroptosis by promoting TLR7, CGAS, STING, RIG-I, or MAVS signaling upon bacterial or viral infection.
“(2) TLR7, cyclic GMP-AMP synthase (CGAS), transmembrane protein 173 (TMEM173; best known as STING), DExD/H-box helicase 58 (DDX58; best known as RIG-I), or mitochondrial antiviral signaling protein (MAVS) signaling upon bacterial or viral infection [525, 645]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [645]
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References 51 · Cited by 380
- Authors
- Man, S. M., Karki, R., Malireddi, R. K. S., Neale, G., Vogel, P., Yamamoto, M., Lamkanfi, M., & Kanneganti, T.-D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- The University of Osaka (JP)
- Vlaams Instituut voor Biotechnologie (BE)
- Corresponding author
- Kanneganti, Thirumala-Devi
- ORCID
- Venue
- Nature Immunology
- Published
- 2015-03-16
- Volume
- 16
- Issue
- 5
- Pages
- 467-475
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4406811
- OpenAlex
- W1984632540
- Cited by
- 380
- References
- 51
- Citations by year
- 2026: 19 · 2025: 36 · 2024: 25 · 2023: 35 · 2022: 27 · 2021: 22 · 2020: 50 · 2019: 34 · 2018: 43 · 2017: 39 · 2016: 35 · 2015: 14
- FWCI
- 18.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- St. Jude Children's Research Hospital
- Universität Basel
- American Lebanese Syrian Associated Charities (CA163507, AR056296, AI101935)
- Vlaamse regering
- National Institutes of Health (AI 101935)
- Genentech
- Medical Research Council
- National Health and Medical Research Council
- National Cancer Institute (R01CA163507, CA163507, P30CA021765)
- National Institute of Allergy and Infectious Diseases (AI101935, R01AI101935, R37AI101935)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056296, AR-056296)
- FP7 Ideas: European Research Council (281600)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- IRF1, AIM2 inflammasome, guanylate-binding proteins, Francisella novicida, cytosolic bacteria, cGAS-STING pathway, type I interferon, DNA sensing, double-stranded DNA, cytomegalovirus, intracellular bacterial killing, DNA release, host defense
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Bacteriolysis, Cells, Cultured, DNA, DNA-Binding Proteins, DNA, Bacterial, Francisella tularensis, Gene Expression Regulation, Interferon Type I, Nucleotidyltransferases, Tularemia, Mice, Knockout, GTP-Binding Proteins, Interferon Regulatory Factor-1, Mice, Inflammasomes
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