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Gasdermins, Executors of Pyroptosis: A Decade in Perspective
Bowen Zhou1,2, Derek Abbott1,3
1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Abstract:
Pyroptosis is a molecularly defined pathway of cell death and lysis relying on formation of membrane pores by the family of gasdermin proteins. Since the characterization of prototypical gasdermin D in 2015, intense effort in the past decade has shed light on protease-dependent activation of these agents of cellular demise in human health and disease, although cell death-independent functions do exist. Numerous regulatory mechanisms ranging from posttranslational modification, control of expression, and overlap in activation systems have been described, but pharmacologic control of gasdermins is still in its infancy. Thus, gasdermin-specific targeting in disease has not yet been achieved outside of a few select cases. This review summarizes these findings broadly from a perspective of biological mechanisms and highlights the forthcoming challenges hindering bench-to-bedside adoption of this knowledge.
Insights
Pyroptosis, a cell death pathway involving gasdermin proteins, is increasingly understood. However, therapeutic targeting of gasdermins for diseases remains challenging, limiting clinical applications.
Area of Science:
- Cellular Biology
- Molecular Mechanisms
- Immunology
Background:
- Pyroptosis is a programmed cell death pathway characterized by membrane pore formation.
- Gasdermin proteins are key executioners of pyroptosis, with gasdermin D being extensively studied.
- Recent research has elucidated protease-dependent activation and cell death-independent functions of gasdermins.
Purpose of the Study:
- To review the biological mechanisms of pyroptosis and gasdermin protein function.
- To highlight the current state of pharmacologic control over gasdermins.
- To identify challenges in translating gasdermin research into clinical applications.
Main Methods:
- Literature review of studies on pyroptosis and gasdermin proteins.
- Analysis of regulatory mechanisms including posttranslational modifications and gene expression.
- Evaluation of existing and potential therapeutic strategies targeting gasdermins.
Main Results:
- Gasdermin proteins mediate pyroptosis through pore formation, crucial in health and disease.
- Multiple regulatory mechanisms control gasdermin activity, but pharmacologic control is limited.
- Despite significant mechanistic insights, clinical translation of gasdermin targeting is nascent.
Conclusions:
- Understanding gasdermin-mediated pyroptosis is advancing rapidly.
- Significant hurdles exist in developing effective gasdermin-specific therapies for diseases.
- Future research should focus on overcoming bench-to-bedside challenges for clinical translation.
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