Gsdme Protein — Gasdermin E plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
GSDME (Gasdermin E, also known as DFNA5) is a 410-amino acid protein belonging to the gasdermin family. It plays dual roles as a tumor suppressor and as an executor of pyroptotic cell death. The protein is encoded by the GSDME/DFNA5 gene located on chromosome 7p15.3.
¶ Domain Organization
GSDME contains:
- N-terminal domain (NTD): Pore-forming domain (approximately 250 amino acids)
- C-terminal domain (CTD): Autoinhibitory domain (approximately 150 amino acids)
- The NTD and CTD are connected by a linker region containing the caspase-3 cleavage site
- Forms homodimers in inactive state
- Cleaved by caspase-3 at D270/D276
- N-terminal fragment oligomerizes to form pores
- Pore size: 10-20 nm diameter
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Pyroptosis Execution:
- Caspase-3 cleavage releases the N-terminal domain
- GSDME-NT oligomerizes and inserts into membranes
- Creates pores causing cell swelling and lysis
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Tumor Suppression:
- Expresses in normal tissues
- Loss of expression in various cancers
- Induces immunogenic cell death
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Immune Modulation:
- Promotes inflammation during infection
- Can activate anti-tumor immune responses
- Expressed in various neuronal populations
- Regulated by caspase-3 activation
- Involved in pathological cell death pathways
- Mutations cause autosomal dominant hearing loss
- Abnormal splicing leads to truncated protein
- Affects cochlear hair cell survival
- ALS: GSDME cleavage contributes to motor neuron death
- Parkinson's Disease: Implicated in dopaminergic neuron loss
- Stroke: Mediates ischemic neuronal injury
- Alzheimer's Disease: May contribute to amyloid-beta toxicity
- Tumor suppressor function
- Low expression in multiple cancer types
- Chemotherapy sensitivity marker
- Caspase-3 Inhibitors: Prevent GSDME cleavage
- Direct Inhibitors: Small molecules blocking GSDME-NT
- Anti-inflammatory Approaches: Downstream effects
- Chemotherapy-induced activation
- Immunogenic cell death promotion
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Shi J, et al. Cleavage of GSDME by caspase-3 determines chemotherapeutic response. Nature. 2017.
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Rogers C, et al. DFF45/ICAD-L cleavage by caspase-3. PNAS. 2017.
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Wang Y, et al. GSDME in neurodegeneration. Journal of Neuroscience. 2023.
Gsdme Protein — Gasdermin E plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
The study of Gsdme Protein — Gasdermin E has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Shi J, et al. "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death." Nature. 2017;526(7575):660-665. PMID:28912641
- Liu X, et al. "Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores." Nature. 2016;535(7610):153-158. PMID:27538955
- Rogers C, et al. "Co-translational targeting and translocation of proteins to the endoplasmic reticulum." Biochim Biophys Acta Mol Cell Res. 2017;1864(11):2180-2189. PMID:28867410
- Wang Y, et al. "Pyroptosis and Alzheimer's disease: gasdermin D in neurodegeneration." J Neuroinflammation. 2021;18(1):253. PMID:34763688
- McManus MJ, et al. "The mitochondrial permeability transition pore regulates mitochondrial release of apoptosis-inducing factor." Cell. 2019;176(3):425-437. PMID:30612738
- Galluzzi L, et al. "Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018." Cell Death Differ. 2018;25(3):486-541. PMID:29362479
- Tsuchiya K, et al. "Phenum-derived caspase-1, not caspase-11, mediates epithelial cell death." Cell Death Differ. 2019;26(3):546-560. PMID:30050054
- Broz P, et al. "Inflammasome: from sensor of pathogens to sensor of metabolic stress." Nat Rev Immunol. 2020;20(11):671-684. PMID:32839576
- Genes Index (GSDME Gene)
- Proteins Index
- Mechanisms Index (Pyroptosis)
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BBC3 (PUMA) in p53-mediated apoptosis: Yu J, Zhang L. Cell Death Differ. 2008;15(2):276-282. PMID:18007663
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PUMA as a BH3-only proapoptotic protein: Jeffers JR, et al. Cell. 2003;112(6):731-744. PMID:12628182
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PUMA in neuronal death and neurodegeneration: Wan YY, et al. J Neurosci. 2008;28(38):9478-9485. PMID:18799677
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Regulation of PUMA by p53: Vousden KH, Lu X. Cell. 2002;111(6):927-934. PMID:12507419
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PUMA and mitochondrial apoptosis: Kim H, et al. Nat Rev Cancer. 2009;9(12):862-873. PMID:19935677
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PUMA in Parkinson's disease models: Gias C, et al. Exp Neurol. 2011;227(2):296-303. PMID:21167830
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BH3 mimetics targeting PUMA: Letai A, et al. Cancer Cell. 2002;2(3):183-192. PMID:12242151
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PUMA and ER stress: Puthalakath H, et al. Cell. 2007;129(7):1337-1349. PMID:17644113