Cited by 2,285Inflammasome and immune disordersImmune Response and InflammationCell death mechanisms and regulation

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Inflammatory caspases are innate immune receptors for intracellular LPS

Shi, Jianjin, Zhao, Yue, Wang, Yupeng, Gao, Wenqing, Ding, Jingjin, Li, Peng, Hu, Liyan, Shao, Feng·2014·Nature

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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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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
ORCID: Shi, Jianjin
Zhao, Yue
Wang, Yupeng
Gao, Wenqing
Ding, Jingjin
Li, Peng
Hu, Liyan
Shao, Feng
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2014-08-06
Volume: 514
Issue: 7521
Pages: 187-192
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature13683
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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Inflammatory caspases are innate immune receptors for intracellular LPS

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