Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
Abstract
Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme-/- (also known as Dfna5-/-) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.
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Pyroptosis generally relies on activation of one or more caspases, including CASP1, CASP3, murine CASP11, and human CASP4 and CASP5, depending on the initiating stimulus.
“At a molecular level, pyroptosis generally relies on the activation of one or more caspases, including CASP1, CASP3, murine CASP11, and its human homologs CASP4 and CASP5, depending on the initiating stimulus [612, 613].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [613]
Activation of GSDME/DFNA5 by CASP3 contributes to side effects of multiple chemotherapeutic agents, at least in mice.
“the activation of GSDME/DFNA5 by CASP3 contributes to the side effects of multiple chemotherapeutic agents, at least in mice [613].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [613]
In GSDME/DFNA5-dependent pyroptosis, CASP3 is responsible for proteolytic cleavage of GSDME/DFNA5, which precipitates pyroptosis rather than apoptosis.
“In this setting, CASP3 is responsible for the proteolytic cleavage of GSDME/DFNA5, which precipitates in pyroptosis rather than apoptosis [39, 613].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [613]
The N-terminal domains of other gasdermin family members, including GSDMA, GSDMB, GSDMC, GSDME/DFNA5, and GSDMA3, resemble GSDMD as they display pore-forming and pyroptotic activity.
“the (shared) N-terminal domains of other members of the gasdermin family, including GSDMA, GSDMB, GSDMC, GSDME/DFNA5, and GSDMA3 (which is encoded by the mouse—but not the human—genome), resemble those of GSDMD as they display pore-forming and pyroptotic activity [39, 613, 626, 629].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [613]
Pyroptotic RCD dependent on GSDME-N/DFNA5-N can be elicited by multiple challenges including TNF, DNA-damaging chemotherapeutic agents, and/or vesicular stomatitis virus infection.
“two recent studies demonstrate the existence of an instance of pyroptotic RCD dependent on GSDME-N/DFNA5-N that can be elicited by multiple challenges, including TNF, various DNA-damaging chemotherapeutic agents, and/or infection with the vesicular stomatitis virus [39, 613].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [613]
GSDME/DFNA5 is often silenced in malignant cells but expressed by their normal counterparts.
“As GSDME/DFNA5 is often silenced in malignant cells but expressed by their normal counterparts”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [613]
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- Authors
- Wang, Y., Gao, W., Shi, X., Ding, J., Liu, W., He, H., Wang, K., & Shao, F.
- Affiliations
- National Institute of Biological Sciences, Beijing (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Shao, Feng
- Venue
- Nature
- Published
- 2017-05-01
- Volume
- 547
- Issue
- 7661
- Pages
- 99-103
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2608687752
- Cited by
- 3,199
- References
- 29
- Citations by year
- 2026: 375 · 2025: 508 · 2024: 538 · 2023: 531 · 2022: 496 · 2021: 331 · 2020: 185 · 2019: 136 · 2018: 68 · 2017: 27 · 2013: 1
- FWCI
- 46.44
- 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
- Academy of Medical Sciences
- Chinese Academy of Sciences
- Chinese Academy of Medical Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- pyroptosis, caspase-3, gasdermin E, gasdermin D, chemotherapy toxicity, apoptosis, TNF-α, membrane perforation, cancer chemotherapy
- MeSH terms
- Pyroptosis, Gasdermins, Animals, Antineoplastic Agents, Humans, Lipopolysaccharides, Mice, Inbred C57BL, Peptide Fragments, Receptors, Estrogen, Caspase 1, Cell Line, Tumor, Mice, Caspase 3
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