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'Hints' in the killer protein gasdermin D: unveiling the secrets of gasdermins driving cell death
Shiqiao Qiu1,2, Jing Liu3, Feiyue Xing1,2
1Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.
Abstract:
Pyroptosis is a lytic form of cell death distinguished from apoptosis, ferroptosis, necrosis, necroptosis, NETosis, oncosis, pyronecrosis and autophagy. Proinflammatory caspases cleave a gasdermin D (GSDMD) protein to generate a 31 kDa N-terminal domain. The cleavage relieves the intramolecular inhibition on the gasdermin-N domain, which then moves to the plasma membrane to exhibit pore-forming activity. Thus, GSDMD acts as the final and direct executor of pyroptotic cell death. Owing to the selective targeting of the inner leaflet of the plasma membrane with the pore-forming that determines pyroptotic cell death, GSDMD could be a potential target to control cell death or extracellular bacterial infections. Intriguingly, other gasdermin family members also share similar N-terminal domains, but they present different cell death programs. Herein, we summarize features and functions of the novel player proteins in cell death, including GSDMD triggering pyroptosis, Gsdma3/GSDMA initiating autophagy/apoptosis and DFNA5 inducing apoptosis/secondary necrosis. The gasdermin N terminus appears to be a novel pore-forming protein. This provides novel insight into the underlying roles and mechanisms of lytic or nonlytic forms of programmed cell death, as well as their potential applications in inflammation-associated diseases.
Insights
Pyroptosis, a lytic cell death, is executed by gasdermin D (GSDMD) pore formation. Other gasdermins also mediate distinct cell death pathways, offering therapeutic targets for inflammatory diseases.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Pyroptosis is a distinct lytic programmed cell death pathway.
- Gasdermin D (GSDMD) is the direct executor of pyroptosis.
- Other gasdermin family members are implicated in various cell death processes.
Purpose of the Study:
- To review the features and functions of gasdermin family members in cell death.
- To highlight GSDMD's role in pyroptosis execution.
- To explore the potential of gasdermins as therapeutic targets.
Main Methods:
- Literature review of programmed cell death mechanisms.
- Analysis of gasdermin protein family functions.
- Summary of GSDMD's pore-forming activity.
Main Results:
- GSDMD cleavage by caspases generates a pore-forming N-terminal domain, executing pyroptosis.
- Gsdma3/GSDMA and DFNA5 induce apoptosis or autophagy.
- Gasdermin N-termini are novel pore-forming domains.
Conclusions:
- Gasdermin family members orchestrate diverse cell death programs.
- GSDMD's pore-forming activity is central to pyroptosis.
- Targeting gasdermins offers potential for treating inflammatory diseases and infections.