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Precise Orchestration of Gasdermins' Pore-Forming Function by Posttranslational Modifications in Health and Disease

Haiyang Jiang1, Peizhao Liu2, Jiaqi Kang2

  • 1Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing 210000, China.

International Journal of Biological Sciences
|October 2, 2023
PubMed

Insights

Gasdermins (GSDMs) are key to pyroptosis, balancing host defense and inflammation. Their precise regulation via posttranslational modifications (PTMs) is crucial for controlling cell death and immunity.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Gasdermins (GSDMs) are critical effectors of pyroptosis, a programmed cell death pathway.
  • GSDMs are involved in host defense, immunity, and cancer, but their dysregulation causes inflammation and tissue damage.
  • Proper GSDM activity requires intricate regulation throughout their lifecycle, from autoinhibition to membrane repair.

Purpose of the Study:

  • To provide a comprehensive review of Gasdermin regulation in pyroptosis.
  • To elucidate the mechanisms of GSDM activation and function.
  • To summarize the role of posttranslational modifications (PTMs) in governing GSDM activity.

Main Methods:

  • Literature review focusing on Gasdermin function and regulation.
  • Analysis of proteolytic cleavage sites and their impact on GSDM activity.
  • Summary of diverse posttranslational modifications (PTMs) affecting GSDMs.
  • Discussion of GSDM-mediated membrane permeabilization and pore formation.

Main Results:

  • GSDM activity is tightly controlled through multiple mechanisms, including autoinhibitory domains and proteolytic cleavage.
  • Posttranslational modifications (PTMs) represent a major regulatory layer, influencing GSDM cleavage, localization, and pore formation.
  • Proteases play a dual role, either activating or inhibiting GSDM function depending on the specific protease and context.
  • GSDM oligomerization, membrane translocation, and pore formation are dynamic processes subject to extensive regulation.

Conclusions:

  • GSDM-mediated pyroptosis is a finely tuned process essential for host defense but requiring strict regulation to prevent pathology.
  • Posttranslational modifications (PTMs) are central to the dynamic modulation of GSDM function, impacting all stages of pyroptosis.
  • Understanding GSDM regulation by proteases and PTMs is crucial for developing therapeutic strategies targeting inflammatory diseases and cancer.
Keywords:
alternative splicingdynamical regulationgasderminposttranslational modificationspyroptosis

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