Gasdermins, Executors of Pyroptosis: A Decade in Perspective

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.