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TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization

Wenqing Gao1, Yuanyuan Li1, Xuehe Liu1

  • 1Department of Neurology, Huashan Hospital and Institute of Neurology, State Key Laboratory of Genetic Engineering, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China.

Cell Death and Differentiation
|September 13, 2021
PubMed

Insights

Tripartite motif protein TRIM21 positively regulates Gasdermin-D (GSDMD)-driven pyroptosis. TRIM21 deficiency protects against inflammation and colitis, suggesting TRIM21 as a therapeutic target for inflammatory diseases.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Gasdermin-D (GSDMD) is a key mediator of pyroptosis, a programmed cell death pathway crucial for host defense.
  • Existing knowledge lacks mechanisms for regulating GSDMD activity beyond caspase cleavage.

Purpose of the Study:

  • To investigate novel regulatory mechanisms of GSDMD-dependent pyroptosis.
  • To identify potential therapeutic targets for inflammation-associated diseases.

Main Methods:

  • Co-immunoprecipitation assays to study protein interactions.
  • Cellular assays to assess pyroptosis and cell death.
  • In vivo studies using TRIM21-deficient mice.

Main Results:

  • Tripartite motif protein TRIM21 interacts with GSDMD through its PRY-SPRY domain.
  • TRIM21 stabilizes GSDMD expression in resting cells and promotes GSDMD-N aggregation during pyroptosis.
  • TRIM21 deficiency reduces cell death upon inflammasome activation and protects mice from inflammatory conditions like colitis.

Conclusions:

  • TRIM21 acts as a positive regulator of GSDMD-mediated pyroptosis.
  • TRIM21 plays a significant role in inflammatory responses.
  • TRIM21 inhibition may offer a therapeutic strategy for inflammatory diseases.

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