| Gasdermin E Protein |
|---|
| Symbol | GSDME / DFNA5 |
| Full Name | Gasdermin E (Deafness, Autosomal Dominant 5) |
| Gene | [GSDME](/genes/gsdme) (DFNA5) |
| UniProt ID | [O60443](https://www.uniprot.org/uniprotkb/O60443) |
| Molecular Weight | 55.4 kDa |
| Length | 496 amino acids |
| Subcellular Location | Cytoplasm, plasma membrane (upon activation) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), Deafness DFNA5, Cancer |
--- is a protein encoded by the GSDME gene that ### Pyroptosis Induction. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Gasdermin E (GSDME, formerly DFNA5) is a member of the gasdermin family with pore-forming capability:
¶ Domain Architecture
- N-terminal domain (NTD) (residues 1-270): Pore-forming domain
- Linker region (residues 271-287): Contains caspase-3 cleavage site
- C-terminal domain (CTD) (residues 288-496): Autoinhibitory domain
- Similar to GSDMD, CTD masks the NTD in the full-length protein
- Cleavage by caspase-3 releases the cytotoxic NTD
- NTD forms pores with similar structure to GSDMD NTD
- Originally identified as deafness gene DFNA5
- Expressed in cochlea, brain, and other tissues
- Low basal expression in many cell types, inducible by p53
GSDME mediates a secondary form of pyroptosis:
- Caspase-3 cleavage: Unlike GSDMD, GSDME is cleaved by executioner caspase-3
- Apoptosis-to-pyroptosis switch: Converts apoptosis to pyroptosis when cleaved
- Secondary necrosis: Responsible for secondary necrosis after apoptosis
- Inner ear function: Required for normal cochlear function
- p53 target: GSDME expression is induced by p53
- Tumor suppression: May function as tumor suppressor
Emerging evidence links GSDME to AD:
- Caspase-3 activation: AD brains show elevated caspase-3 activity
- Pyroptosis contribution: GSDME may contribute to neuronal pyroptosis
- Secondary necrosis: May mediate secondary necrosis in advanced AD
- Inflammation: GSDME pores release DAMPs and amplify inflammation
- Caspase-3 dependent: Many neurodegenerative conditions involve caspase-3 activation
- Switch to pyroptosis: GSDME converts apoptotic neurons to pyroptotic death
- Inflammatory amplification: Pyroptosis releases inflammatory mediators
- Chemotherapy side effects: Some chemotherapies activate GSDME in neurons
- Peripheral neuropathy: GSDME may contribute to chemotherapy-induced neuropathy
- Cognitive effects: Potential role in "chemo brain"
| Context |
Activator |
Cleavage Site |
| Apoptosis |
Caspase-3 (downstream of apoptosome) |
D270 |
| Chemotherapy |
Caspase-3 (DNA damage response) |
D270 |
| TNF signaling |
Caspase-3 (extrinsic pathway) |
D270 |
- NTD binds to inner leaflet phospholipids
- Forms ~15 nm pores in plasma membrane
- Allows IL-1β release and osmotic lysis
- Creates conduit for DAMP release
| Feature |
GSDME |
GSDMD |
| Primary caspase |
Caspase-3 |
Caspase-1/4/5/11 |
| Activation pathway |
Apoptotic/Extrinsic |
Inflammasome |
| Typical context |
Secondary necrosis, chemotherapy |
Infection, sterile inflammation |
| Tissue expression |
Low/inducible |
Higher/myeloid |
- Chemotherapy sensitization: GSDME expression enhances chemo efficacy
- Immunogenic cell death: GSDME-mediated pyroptosis releases tumor antigens
- Combination therapy: p53 activators + chemotherapy to induce GSDME
- Caspase-3 inhibitors: Block GSDME cleavage
- GSDME-specific inhibitors: Prevent pore formation
- p53 modulation: Reduce GSDME induction in neurons
- DFNA5-related deafness: Understanding GSDME function aids therapy development
- Gene therapy: Potential for DFNA5-related hearing loss
| Interacting Protein |
Function |
Disease Relevance |
| Caspase-3 |
Cleaves GSDME at D270 |
Apoptosis, chemotherapy |
| p53 |
Transcriptional activator of GSDME |
Cancer, DNA damage |
| BCL2 family |
Regulates apoptotic pathway upstream |
Neurodegeneration |
| Apaf1 |
Forms apoptosome |
Intrinsic apoptosis |