Calpain drives pyroptotic vimentin cleavage, intermediate filament loss, and cell rupture that mediates immunostimulation
Open accessAbstract
Significance: Pyroptosis is a form of inflammatory cell death. It is driven by plasma membrane pore formation that is thought to rupture cells through osmotic influx, thereby releasing intracellular content that initiates an inflammatory response to fight acute infection and tissue damage. However, when chronic or unregulated, this process can drive autoimmune disease and cancer. Here, we show that pyroptotic cells do not undergo rupture in culture. Instead, the calcium-dependent protease calpain destroys intermediate filaments, which provide mechanical resilience to cells. As a result, cells are susceptible to rupture by mechanical disruption from shear stress or compression as occurs in the blood stream or within tissues. Thus, our data reveal potential targets for the therapeutic intervention of autoimmune diseases and cancer.
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Programmed necrosis (necroptosis) and pyroptosis induce active release of intact mitochondria into extracellular milieu.
“Moreover, programmed necrosis (known as necroptosis) and pyroptosis induce the active release of intact mitochondria into the extracellular milieu211.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [211]
The section “Rupture of Pyroptotic Cells Releases Macro-DAMPs and Is” (page unavailable) reports mitochondrial DNA and CoxI in supernatants after pyroptotic cells were ruptured by pipetting, and says mitochondrial release from necroptotic cells had been reported. It does not establish that either process actively releases intact mitochondria; its pyroptosis finding depends on cell rupture induced by external shear stress. (LLM, conf=0.88)
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The role of mitochondria in rheumatic diseases
Becker, Y. L. C., Duvvuri, B., Fortin, P. R., Lood, C., & Boilard, E. (2022) · Nature Reviews Rheumatology · doi:10.1038/s41584-022-00834-z · Cited by 81 · see citing works
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- Authors
- Davis, M. A., Fairgrieve, M. R., Den Hartigh, A., Yakovenko, O., Duvvuri, B., Lood, C., Thomas, W. E., Fink, S. L., & Gale, M.
- Affiliations
- University of Washington (US)
- Department of Laboratory Medicine, University of Washington, Seattle, WA 98195;
- Corresponding author
- Gale, Michael
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-02-22
- Volume
- 116
- Issue
- 11
- Pages
- 5061-5070
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6421439
- OpenAlex
- W2916651092
- Cited by
- 104
- References
- 52
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 10 · 2023: 12 · 2022: 19 · 2021: 15 · 2020: 16 · 2019: 7
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (AI127463, AI118916, AI100625, AI108319, AI104002, K08 AI119142, AI106987)
- Alliance for Lupus Research (519414)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- pyroptosis, calpain, intermediate filaments, cell rupture, mechanical resilience, cytoskeleton disruption, gasdermin D, ASC specks, HMGB1, IL-1β, immunostimulation, shear stress, mitochondrial release, bacterial release, programmed cell death
- MeSH terms
- Alarmins, Pyroptosis, THP-1 Cells, Gasdermins, Calpain, Cytoskeleton, Cytosol, Humans, Immunization, Intermediate Filaments, Neoplasm Proteins, Stress, Mechanical, Vimentin, Compressive Strength, Caspase 1, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, CARD Signaling Adaptor Proteins, Inflammasomes
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