Inflammatory caspases are innate immune receptors for intracellular LPS
Abstract
The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by human caspase-4 that could functionally complement murine caspase-11. Human caspase-4 and the mouse homologue caspase-11 (hereafter referred to as caspase-4/11) and also human caspase-5, directly bound to LPS and lipid A with high specificity and affinity. LPS associated with endogenous caspase-11 in pyroptotic cells. Insect-cell purified caspase-4/11 underwent oligomerization upon LPS binding, resulting in activation of the caspases. Underacylated lipid IVa and lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) could bind to caspase-4/11 but failed to induce their oligomerization and activation. LPS binding was mediated by the CARD domain of the caspase. Binding-deficient CARD-domain point mutants did not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections. The function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation.
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CASP11, CASP4, and CASP5 trigger pyroptosis upon sensing cytosolic LPS in monocytes and other cell types.
“Further experimental observations confirmed that CASP11, CASP4, and CASP5 trigger pyroptosis upon sensing cytosolic LPS [609 622–624], in monocytes as well as in other cell types [609, 625].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [609]
LPS-induced pyroptosis involves physical interaction of LPS or its lipid moiety with the CARD domain of CASP11, CASP4, or CASP5, resulting in caspase oligomerization and activation.
“LPS-induced pyroptosis involves the physical interaction of LPS (or its lipid moiety) with the CARD domain of CASP11, CASP4, or CASP5, a highly specific binding resulting in caspase oligomerization and consequent activation [609].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [609]
Pyroptosis can occur in cell types other than cells from the monocytic lineage.
“(2) can also occur in cell types other than cells from the monocytic lineage [609]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [609]
CASP11, CASP4, and CASP5 act as bona fide PRRs for cytosolic LPS.
“Thus, CASP11, CASP4, and CASP5 act as bona fide PRRs for cytosolic LPS.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [609]
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- Authors
- Shi, J., Zhao, Y., Wang, Y., Gao, W., Ding, J., Li, P., Hu, L., & Shao, F.
- Affiliations
- Peking University (CN)
- National Institute of Biological Sciences, Beijing (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Shao, Feng
- Venue
- Nature
- Published
- 2014-08-06
- Volume
- 514
- Issue
- 7521
- Pages
- 187-192
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2068619092
- Cited by
- 2,285
- References
- 41
- Citations by year
- 2026: 190 · 2025: 205 · 2024: 231 · 2023: 277 · 2022: 254 · 2021: 227 · 2020: 193 · 2019: 162 · 2018: 158 · 2017: 131 · 2016: 128 · 2015: 103 · 2014: 23
- FWCI
- 52.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Tsinghua University
- University of British Columbia
- National Key Research and Development Program of China
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- caspase-4, caspase-5, non-canonical inflammasome, pyroptosis, pattern recognition receptors, CARD domain, lipid A, endotoxic shock, intracellular bacterial infection, innate immunity, inflammatory cell death
- MeSH terms
- Animals, Cells, Cultured, Enzyme Activation, Epithelial Cells, Genetic Complementation Test, Humans, Immunity, Innate, Inflammation, Lipid A, Lipopolysaccharides, Macrophages, Necrosis, Protein Binding, Rhodobacter sphaeroides, Substrate Specificity, Keratinocytes, Cell Death, Caspases, Surface Plasmon Resonance, Mutant Proteins, Mice, Caspases, Initiator, Protein Multimerization
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