The PYRIN-CARD Protein ASC Is an Activating Adaptor for Caspase-1
Open accessAbstract
The PYRIN and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the apoptotic and inflammatory signaling pathways. Here we show that the PYRIN-CARD protein ASC functions as a caspase-1-activating adaptor. ASC interacted specifically with procaspase-1 via CARD-CARD interactions and induced its oligomerization. Consistent with these results ectopic expression of full-length ASC, but not its isolated CARD or PYRIN domain, with procaspase-1 induced activation of procaspase-1 and processing of pro-interleukin-1beta in transfected cells. Substitution of the PYRIN domain of ASC with an inducible FKBP12 oligomerization domain produced a molecule that can induce caspase-1 activation in response to stimulation with the oligomerization drug AP20187, suggesting that the PYRIN domain functions as an oligomerization domain, whereas the CARD domain functions as the effector domain in the caspase-1 activation pathway. Furthermore stable expression of an isolated CARD of ASC in THP-1 cells diminished interleukin-1beta generation in response to pro-inflammatory cytokines. These results indicate that ASC is involved in the caspase-1 signaling pathway by mediating the assembly of a caspase-1-inflammasome signaling complex in response to pro-inflammatory cytokine stimulation.
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Pro-caspase-1 undergoes proximity-induced autoproteolysis, leading to active caspase-1 processing pro-IL-1β and pro-IL-18 into their mature forms and subsequent secretion.
“Pro-caspase-1 then undergoes proximity-induced autoproteolysis, which leads to active caspase-1 processing pro-IL-1β and pro-IL-18 into their mature forms IL-1β and IL-18 and the subsequent secretion of these cytokines [55, 58, 61–63]”
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- Authors
- Srinivasula, S. M., Poyet, J.-L., Razmara, M., Datta, P., Zhang, Z., & Alnemri, E. S.
- Affiliations
- Thomas Jefferson University (US)
- Corresponding author
- Alnemri, Emad S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 277
- Issue
- 24
- Pages
- 21119-21122
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2014602273
- Cited by
- 573
- References
- 1
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 13 · 2023: 29 · 2022: 27 · 2021: 45 · 2020: 27 · 2019: 28 · 2018: 25 · 2017: 22 · 2016: 24 · 2015: 28 · 2014: 25 · 2013: 25 · 2012: 17
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca085421-05)
- National Institute on Aging (AG14357, R01AG014357)
- National Cancer Institute (CA85421)
- 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
- ASC, pyrin domain, CARD domain, caspase-1 activation, inflammasome, interleukin-1β processing, inflammatory cytokines, THP-1 cells, AP20187
- MeSH terms
- Pyrin, NLR Family, Pyrin Domain-Containing 3 Protein, Blood Proteins, Carrier Proteins, Cell Line, Cells, Cultured, Cytoskeletal Proteins, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Genes, Dominant, Genetic Vectors, Glutathione Transferase, Humans, Interleukin-1, Precipitin Tests, Protein Binding, Proteins, Transfection, Immunoblotting, Protein Structure, Tertiary, Caspase 1, CARD Signaling Adaptor Proteins
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