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Related Concept Videos

Protein Modifications in the RER01:26

Protein Modifications in the RER

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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
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GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Updated: Jun 28, 2025

Live Imaging Assay for Assessing the Roles of Ca2+ and Sphingomyelinase in the Repair of Pore-forming Toxin Wounds
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Live Imaging Assay for Assessing the Roles of Ca2+ and Sphingomyelinase in the Repair of Pore-forming Toxin Wounds

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ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.

Gang Du1,2, Liam B Healy3,4, Liron David5,6,7

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. gdu@crystal.harvard.edu.

Nature
|April 10, 2024
PubMed
Summary
This summary is machine-generated.

Gasdermin D (GSDMD) is palmitoylated, a modification essential for pore formation during pyroptosis. This reversible palmitoylation acts as a crucial switch for GSDMD activation, challenging previous notions of cleavage being the sole trigger.

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Area of Science:

  • Cellular Biology
  • Immunology
  • Biochemistry

Background:

  • Gasdermin D (GSDMD) is a key effector in inflammasome activation, mediating cytokine secretion and pyroptosis by forming transmembrane pores.
  • GSDMD pore formation has been primarily attributed to its N-terminal domain (GSDMD-NT) generated by caspase cleavage.

Purpose of the Study:

  • To investigate the role of post-translational modifications beyond cleavage in GSDMD activation.
  • To identify novel regulatory mechanisms controlling GSDMD-mediated pyroptosis.

Main Methods:

  • Assessing GSDMD palmitoylation at Cys191 using biochemical assays.
  • Investigating the impact of S-palmitoylation on GSDMD pore formation and pyroptosis using cleavage-deficient mutants and liposome leakage assays.
  • Identifying GSDMD palmitoyltransferases (ZDHHC5, ZDHHC9) and analyzing their regulation by inflammasome activation and reactive oxygen species (ROS).

Main Results:

  • GSDMD Cys191 is S-palmitoylated, and this modification is critical for pore formation, independent of caspase cleavage.
  • Mitochondria-derived reactive oxygen species (ROS) enhance GSDMD palmitoylation.
  • Palmitoylated GSDMD, including cleavage-deficient forms, induces liposome leakage and pyroptosis, with palmitoylation acting as a key activation switch for the gasdermin family.

Conclusions:

  • Reversible S-palmitoylation is a critical checkpoint for Gasdermin D pore formation and pyroptosis, acting as a general activation switch for the gasdermin family.
  • This finding challenges the paradigm that caspase-mediated cleavage is the sole trigger for GSDMD activation.
  • Palmitoylation represents a novel therapeutic target for modulating inflammatory responses.