| Gasdermin D Protein |
|---|
| Symbol | GSDMD |
| Full Name | Gasdermin D |
| Gene | [GSDMD](/genes/gsdmd) |
| UniProt ID | [P57764](https://www.uniprot.org/uniprotkb/P57764) |
| Molecular Weight | 52.8 kDa |
| Length | 487 amino acids |
| Subcellular Location | Cytoplasm, plasma membrane (upon activation) |
| PDB Structures | [6N9O](https://www.rcsb.org/structure/6N9O), [6VPE](https://www.rcsb.org/structure/6VPE) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Sepsis, Inflammatory diseases |
Gasdermin D is a protein encoded by the GSDMD gene that serves as the central executor of pyroptotic cell death. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Gasdermin D is the central executor of pyroptosis, a pro-inflammatory form of programmed cell death:
¶ Domain Architecture
- N-terminal domain (NTD) (residues 1-242): Pore-forming domain, cytotoxic when cleaved
- Linker region (residues 243-275): Flexible segment containing cleavage sites
- C-terminal domain (CTD) (residues 276-487): Autoinhibitory domain that masks NTD
- In full-length GSDMD, CTD binds and masks the NTD
- This intramolecular interaction prevents pore formation
- Cleavage by inflammatory caspases releases the NTD from inhibition
- NTD monomers oligomerize to form large transmembrane pores
- Each pore contains 16-24 subunits
- Pore diameter: 10-14 nm, sufficient for IL-1β and IL-18 release
- Forms arc-shaped or slit-shaped oligomers on membranes
GSDMD is the essential executor of inflammatory cell death:
- Dormant state: Full-length GSDMD is autoinhibited in the cytoplasm
- Caspase activation: Inflammatory caspases (caspase-1, -4, -5, -11) cleave GSDMD
- NTD release: Cleavage separates NTD from autoinhibitory CTD
- Membrane translocation: NTD translocates to plasma membrane
- Pore formation: NTD oligomerizes into large transmembrane pores
- Cell lysis: Pores cause osmotic swelling and membrane rupture
- Canonical pathway: Caspase-1 (activated by inflammasomes) cleaves GSDMD
- Non-canonical pathway: Caspase-4/5 (human) or caspase-11 (mouse) cleave GSDMD
- Cleavage site: After Asp-275 (FLTD|G sequence)
- GSDMD pores allow passive release of mature cytokines
- Also creates channels for gasdermin-mediated cytokine secretion
- Critical for inflammatory signaling in infection and sterile inflammation
GSDMD-mediated pyroptosis contributes to AD pathology:
- NLRP3 inflammasome activation: Aβ aggregates trigger NLRP3 activation
- GSDMD cleavage: Active caspase-1 cleaves GSDMD in microglia
- Pyroptotic microglia death: GSDMD pores cause microglial lysis
- IL-1β release: GSDMD pores facilitate IL-1β/IL-18 release, amplifying inflammation
- Neuronal damage: IL-1β and other inflammatory mediators damage neurons
- α-synuclein-induced pyroptosis: Fibrillar α-synuclein activates inflammasome
- Microglial pyroptosis: GSDMD activation in microglia contributes to neuroinflammation
- Dopaminergic neuron death: Inflammatory milieu from pyroptosis damages neurons
- Demyelination-associated pyroptosis: GSDMD activation in immune cells
- Blood-brain barrier disruption: GSDMD pores may contribute to BBB breakdown
- Therapeutic target: GSDMD inhibition shows promise in EAE models
¶ Stroke and Traumatic Brain Injury
- Acute neuroinflammation: Rapid GSDMD activation following injury
- Neuronal pyroptosis: Direct GSDMD activation in neurons under severe stress
- Secondary damage: Pyroptosis amplifies inflammatory cascade
| Caspase |
Species |
Context |
Cleavage Site |
| Caspase-1 |
Human/Mouse |
Canonical inflammasome |
D275 |
| Caspase-4 |
Human |
LPS sensing |
D275 |
| Caspase-5 |
Human |
Non-canonical |
D275 |
| Caspase-11 |
Mouse |
Non-canonical |
D276 |
- Lipid binding: NTD binds phosphoinositides (PI(4,5)P2) and cardiolipin
- Membrane insertion: α-helices insert into lipid bilayer
- Oligomerization: 16-24 NTD subunits assemble into pore
- Membrane rupture: Pores destabilize membrane integrity
- Osmotic lysis: Uncontrolled ion/water flux causes cell swelling
- DNA damage: Nuclear envelope pores allow DNA-damaging factors
- Content release: Cytosolic contents including DAMPs are released
- Necrosulfonamide (NSA): Covalently modifies GSDMD C191, blocks pore formation
- Disulfiram: Repurposed drug inhibits GSDMD pore formation
- DMF (dimethyl fumarate): Modifies GSDMD C191, reduces pyroptosis
- GSDMD knockout mice: Protected from inflammasome-mediated pathology
- CRISPR targeting: GSDMD gene editing for inflammatory diseases
- Sepsis: GSDMD inhibition reduces systemic inflammation
- Neuroinflammation: Potential for treating AD, PD, MS
- Autoinflammatory diseases: GSDMD targeting in CAPS and related disorders
| Interacting Protein |
Function |
Disease Relevance |
| Caspase-1 |
Canonical inflammasome effector |
AD, PD, MS |
| Caspase-4/5 |
Non-canonical activation |
Sepsis |
| NLRP3 |
Inflammasome sensor |
AD, gout |
| ASC/PYCARD |
Inflammasome adaptor |
AD, PD |
| IL-1β |
Cytokine release through pores |
Neuroinflammation |