Caspase 3 proteolytically inactivates gasdermin Ec and inhibits pyroptosis in an early vertebrate
Gasdermin represents a family of pore-forming proteins that execute programmed necrotic cell death, pyroptosis. As an ancient family member, gasdermin E (GSDME) exists ubiquitously from fish to mammals. Recently, a new GSDME homolog, designated GSDMEc, was identified exclusively in fish. However, th...
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| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
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| Series: | Comparative Immunology Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950311625000229 |
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| Summary: | Gasdermin represents a family of pore-forming proteins that execute programmed necrotic cell death, pyroptosis. As an ancient family member, gasdermin E (GSDME) exists ubiquitously from fish to mammals. Recently, a new GSDME homolog, designated GSDMEc, was identified exclusively in fish. However, the function and regulation of GSDMEc remain elusive. In the present study, we identified a GSDMEc ortholog in swordtail fish, which exhibits canonical gasdermin two-domain architecture. Similar to its pyroptosis-inducing homologs, swordtail fish GSDMEc could execute pyroptosis via conserved N-terminal domain, whereas the C-terminal domain exerts auto-inhibitory effect on N-terminal domain to maintain the full-length protein non-cytotoxicity. We further explored the proteolytic cleavage of GSDMEc, and found that caspase 3 specifically cleaved GSDMEc at the site within the N-terminal domain, and generated a truncated N-terminal fragment. In accordance with this observation, co-expression of caspase 3 and GSDMEc did not result in pyroptosis, while co-expression of caspase 3 impeded pyroptosis induced by the N-terminal domain of GSDMEc. Collectively, our study reveals the negative regulation of caspase 3/GSDMEc-mediated pyroptosis in swordtail fish, which provides insight into gasdermin functionality and pyroptosis regulation in early vertebrates. |
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| ISSN: | 2950-3116 |