Differential Requirement of P2X7 Receptor and Intracellular K+ for Caspase-1 Activation Induced by Intracellular and Extracellular Bacteria
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Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that plays an important role in host defense and inflammatory diseases. The maturation and secretion of IL-1beta are mediated by caspase-1, a protease that processes pro-IL-1beta into biologically active IL-1beta. The activity of caspase-1 is controlled by the inflammasome, a multiprotein complex formed by NLR proteins and the adaptor ASC, that induces the activation of caspase-1. The current model proposes that changes in the intracellular concentration of K(+) potentiate caspase-1 activation induced by the recognition of bacterial products. However, the roles of P2X7 receptor and intracellular K(+) in IL-1beta secretion induced by bacterial infection remain unknown. Here we show that, in response to Toll-like receptor agonists such as lipopolysaccharide or infection with extracellular bacteria Staphylococcus aureus and Escherichia coli, efficient caspase-1 activation is only triggered by addition of ATP, a signal that promotes caspase-1 activation through depletion of intracellular K(+) caused by stimulation of the purinergic P2X7 receptor. In contrast, activation of caspase-1 that relies on cytosolic sensing of flagellin or intracellular bacteria did not require ATP stimulation or depletion of cytoplasmic K(+). Consistently, caspase-1 activation induced by intracellular Salmonella or Listeria was unimpaired in macrophages deficient in P2X7 receptor. These results indicate that, unlike caspase-1 induced by Toll-like receptor agonists and ATP, activation of the inflammasome by intracellular bacteria and cytosolic flagellin proceeds normally in the absence of P2X7 receptor-mediated cytoplasmic K(+) perturbations.
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Lowering intracellular K+ through efflux is required for Nalp3 activation by every known activator, including MSU.
“In favour of the latter assumption is the recent finding that potassium (K + ) efflux, lowering intracellular K + levels, is a requirement for Nalp3 inflammasome activation triggered by all known activators including MSU (13)(14)(15).”
From Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica (2008) · cites this paper as [14]
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Self-citation
- Authors
- Franchi, L., Kanneganti, T.-D., Dubyak, G. R., & Núñez, G.
- Affiliations
- University of Michigan (US)
- Case Western Reserve University (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 282
- Issue
- 26
- Pages
- 18810-18818
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2012576192
- Cited by
- 356
- References
- 54
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 7 · 2023: 20 · 2022: 12 · 2021: 15 · 2020: 9 · 2019: 8 · 2018: 16 · 2017: 9 · 2016: 16 · 2015: 23 · 2014: 28 · 2013: 29 · 2012: 23
- FWCI
- 12.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Arthritis Foundation
- Pfizer
- National Institutes of Health (AI063331)
- Takeda Oncology
- National Institute of General Medical Sciences (GM-36387, R01GM036387)
- National Institute of Allergy and Infectious Diseases (AI 064748, AI063331, R01AI064748)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 051790)
- 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 › Physiology › Adenosine and Purinergic Signaling
- Keywords
- P2X7 receptor, intracellular potassium, caspase-1 activation, inflammasome, interleukin-1β secretion, ATP, TLR agonists, lipopolysaccharide, Staphylococcus aureus, Escherichia coli, flagellin, intracellular bacteria, Salmonella, Listeria, macrophages, purinergic signaling
- MeSH terms
- Adenosine Triphosphate, Animals, Bacterial Infections, Calcium-Binding Proteins, Cytosol, Escherichia coli Infections, Extracellular Space, Flagellin, Lipopolysaccharides, Listeriosis, Macrophages, Mice, Mutant Strains, Potassium, Salmonella Infections, Salmonella typhimurium, Staphylococcal Infections, Staphylococcus aureus, Receptors, Purinergic P2, Caspase 1, Apoptosis Regulatory Proteins, Mice, Receptors, Purinergic P2X7
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