Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases
Abstract
Lipopolysaccharide from Gram-negative bacteria is sensed in the host cell cytoplasm by a non-canonical inflammasome pathway that ultimately results in caspase-11 activation and cell death. In mouse macrophages, activation of this pathway requires the production of type-I interferons, indicating that interferon-induced genes have a critical role in initiating this pathway. Here we report that a cluster of small interferon-inducible GTPases, the so-called guanylate-binding proteins, is required for the full activity of the non-canonical caspase-11 inflammasome during infections with vacuolar Gram-negative bacteria. We show that guanylate-binding proteins are recruited to intracellular bacterial pathogens and are necessary to induce the lysis of the pathogen-containing vacuole. Lysis of the vacuole releases bacteria into the cytosol, thus allowing the detection of their lipopolysaccharide by a yet unknown lipopolysaccharide sensor. Moreover, recognition of the lysed vacuole by the danger sensor galectin-8 initiates the uptake of bacteria into autophagosomes, which results in a reduction of caspase-11 activation. These results indicate that host-mediated lysis of pathogen-containing vacuoles is an essential immune function and is necessary for efficient recognition of pathogens by inflammasome complexes in the cytosol.
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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 [646]
Stimulation of autophagy is instrumental to prevent excessive IL1B production by sequestering lipopolysaccharide and preventing its recognition in the cytosol through the CASP4/CASP11 inflammasome.
“Although pattern‐recognition receptor activation triggers cytoprotective autophagy, the stimulation of autophagy is instrumental to prevent excessive IL1B production by sequestering lipopolysaccharide and preventing its recognition in the cytosol through the CASP4/CASP11 (caspase 4, apoptosis‐related cysteine peptidase) inflammasome (Meunier et al, 2014).”
From Autophagy in major human diseases (2021) · cites this paper as Meunier et al, 2014
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- Authors
- Meunier, E., Dick, M. S., Dreier, R. F., Schürmann, N., Broz, D. K., Warming, S., Roose-Girma, M., Bumann, D., Kayagaki, N., Takeda, K., Yamamoto, M., & Broz, P.
- Affiliations
- University of Basel (CH)
- Genentech (US)
- The University of Osaka (JP)
- Venue
- Nature
- Published
- 2014-04-16
- Volume
- 509
- Issue
- 7500
- Pages
- 366-370
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1979318608
- Cited by
- 485
- References
- 26
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 24 · 2023: 36 · 2022: 44 · 2021: 36 · 2020: 56 · 2019: 45 · 2018: 50 · 2017: 44 · 2016: 47 · 2015: 43 · 2014: 13
- FWCI
- 20.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- 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
- caspase-11, inflammasome, interferon-inducible GTPases, guanylate-binding proteins, Gram-negative bacteria, type I interferon, galectin-8, autophagy, phagosome, macrophages, non-canonical inflammasome
- MeSH terms
- Animals, Autophagy, Cytosol, Enzyme Activation, Gram-Negative Bacteria, Immunity, Innate, Interferon Type I, Lipopolysaccharides, Phagosomes, Salmonella typhimurium, Vacuoles, Caspases, GTP Phosphohydrolases, Galectins, Mice, Caspases, Initiator, Inflammasomes
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