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Updated: Jun 29, 2025

Acyl-PEGyl Exchange Gel Shift Assay for Quantitative Determination of Palmitoylation of Brain Membrane Proteins
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Acyl-PEGyl Exchange Gel Shift Assay for Quantitative Determination of Palmitoylation of Brain Membrane Proteins

Published on: March 29, 2020

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A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis

Na Zhang1,2, Jian Zhang3, Yuanxin Yang1,2

  • 1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.

Nature Cell Biology
|March 28, 2024
PubMed

Insights

Gasdermin D (GSDMD) activation during pyroptosis is controlled by a palmitoylation-depalmitoylation relay. This process regulates GSDMD pore formation, impacting host defense and sepsis survival.

Area of Science:

  • Cellular Biology
  • Immunology
  • Biochemistry

Background:

  • Gasdermin D (GSDMD) executes pyroptosis, a programmed cell death crucial for fighting infections.
  • GSDMD activation involves caspase-mediated cleavage, releasing GSDMD-NT to form membrane pores and release cytokines.
  • The precise spatial and temporal regulation of GSDMD during pyroptosis is not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling Gasdermin D (GSDMD) activation during pyroptosis.
  • To investigate the role of post-translational modifications in the spatiotemporal control of GSDMD.

Main Methods:

  • Identification of GSDMD as a substrate for S-palmitoylation at C192.
  • Characterization of DHHC7 as the palmitoyl acyltransferase and APT2 as the depalmitoylase involved.
  • Assessment of the impact of modulating palmitoylation/depalmitoylation on pyroptosis and host survival.

Main Results:

  • GSDMD undergoes reversible S-palmitoylation at C192 during pyroptosis.
  • DHHC7-mediated palmitoylation facilitates caspase cleavage of GSDMD.
  • Palmitoylation of GSDMD-NT promotes its membrane translocation, and APT2-mediated depalmitoylation drives pore formation.

Conclusions:

  • A palmitoylation-depalmitoylation relay spatiotemporally controls GSDMD activation.
  • Disrupting this relay suppresses pyroptosis, enhancing survival in lethal septic shock models.
  • This mechanism is critical for effective host defense against pathogens.

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