GSDME

Functional Isoforms

Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.

Activated N-terminal cleavage product CLEAVAGE PRODUCT

ID: GSDME_N_TERMINAL

UNIPROT CHAIN:PRO_0000442786 (residues 1-270)

Proteolytic N-terminal effector, residues 1–270; distinct from alternative splice products and pathogenic truncations.

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Reason: Yeast two-hybrid assays support GSDME–TIFA association. Retain this as non-core binding; its physiological role remains unresolved. Supporting Evidence: PMID:32296183 file:human/GSDME/GSDME-source-evidence.json
GO:0005546 phosphatidylinositol-4,5-bisphosphate binding	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	ACCEPT	Reason: Activated human GSDME-N binds PIP2-containing liposomes; replacing PIP2 with phosphatidylethanolamine abolishes binding. Supporting Evidence: PMID:28459430
GO:0005737 cytoplasm	IEA GO_REF:0000107	TOO GENERAL	Reason: The unextended cytoplasm assertion is broader than retained located_in cytosol annotations. The donor's neuronal extension is preserved separately. Proposed replacements: cytosol Supporting Evidence: file:human/GSDME/GSDME-source-evidence.json
GO:0005829 cytosol	IDA GO_REF:0000052	KEEP AS NON CORE	Reason: HPA reports supported cytosolic staining with two antibodies across human cell lines. Retain this localization; the assay does not resolve cleavage state. Supporting Evidence: file:human/GSDME/GSDME-source-evidence.json
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Reason: UniProt assigns cytosol to the precursor. Retain this inactive pool separately from membrane pore activity. Supporting Evidence: UniProtKB:O60443
GO:0005829 cytosol	TAS Reactome:R-HSA-9647632	KEEP AS NON CORE	Reason: Retain the cytosolic precursor and cleavage-product pools as non-core localization. This event links full-length GSDME and both fragments to cytosol; CASP3 performs the cleavage, while the pore-forming product acts at membranes. Supporting Evidence: Reactome:R-HSA-9647632
GO:0005829 cytosol	TAS Reactome:R-HSA-9647660	KEEP AS NON CORE	Reason: Retain the soluble N-terminal pool as non-core localization. The exact cytosolic GSDME(1–270) input joins a plasma-membrane lipid complex; the input and complex compartments are distinct. Supporting Evidence: Reactome:R-HSA-9647660
GO:0005829 cytosol	TAS Reactome:R-HSA-9710254	KEEP AS NON CORE	Reason: Retain the cytosolic N-terminal input as non-core localization preceding membrane assembly. The target leaf is cytosolic, whereas the resulting lipid-associated oligomer is assigned to plasma membrane. Supporting Evidence: Reactome:R-HSA-9710254
GO:0005829 cytosol	TAS Reactome:R-HSA-9710263	KEEP AS NON CORE	Reason: Retain the cytosolic precursor and cleavage-product pools as non-core localization. The event explicitly links full-length GSDME and both fragments to cytosol; GZMB supplies the protease activity. Supporting Evidence: Reactome:R-HSA-9710263
GO:0005829 cytosol	TAS Reactome:R-HSA-9710306	KEEP AS NON CORE	Reason: Retain the newly synthesized cytosolic protein pool as non-core localization. GSDME protein is the output; the nuclear gene and transcriptional regulators are separate participants. Supporting Evidence: Reactome:R-HSA-9710306
GO:0005829 cytosol	TAS Reactome:R-HSA-9710354	KEEP AS NON CORE	Reason: Retain the cytosolic N-terminal pool as non-core localization. The exact GSDME(1–270) input is cytosolic and its cardiolipin complex is mitochondrial; this does not place the membrane-bound complex in cytosol. Supporting Evidence: Reactome:R-HSA-9710354
GO:0005829 cytosol	TAS Reactome:R-HSA-9710468	KEEP AS NON CORE	Reason: Retain established cytosolic localization as a non-core precursor/product pool. This event specifically represents GSDME variants; its summary does not establish that they fail to bind PIPs. Supporting Evidence: Reactome:R-HSA-9710468
GO:0005886 plasma membrane	EXP PMID:28045099 Cleavage of DFNA5 by caspase-3 during apoptosis mediates pro...	ACCEPT	Reason: Activated GSDME-N targets the plasma membrane; imaging uses the F2A variant, supported by wild-type membrane fractionation. Supporting Evidence: PMID:28045099
GO:0005886 plasma membrane	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	ACCEPT	Reason: The active N-terminal product forms membrane pores; plasma-membrane association applies to this processed product. Supporting Evidence: PMID:28459430
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Reason: UniProt assigns plasma membrane to the processed N-terminal product, consistent with the core pore-forming activity. Supporting Evidence: UniProtKB:O60443
GO:0007605 sensory perception of sound	TAS PMID:9771715 Nonsyndromic hearing impairment is associated with a mutatio...	MARK AS OVER ANNOTATED	Reason: The familial exon-8-skipping association establishes a hearing-loss phenotype, without demonstrating participation of normal GSDME in auditory perception. Preserve the disease observation without assigning this physiological process. Supporting Evidence: PMID:9771715 mutation co-segregated with deafness in the family
GO:0008285 negative regulation of cell population proliferation	IDA PMID:18223688 Aberrant promoter methylation and tumor suppressive activity...	KEEP AS NON CORE	Reason: Full-length DFNA5 expression suppresses HCT116 growth and colonies, while two siRNAs increase growth in HCT116 and HEK293. Retain this cellular phenotype without inferring a direct cell-cycle regulator. Supporting Evidence: PMID:18223688
GO:0012501 programmed cell death	IEA GO_REF:0000002	TOO GENERAL	Reason: The family-derived programmed-cell-death assertion is sound, but the independently supported GO:0141201 pyroptotic cell death is a narrower existing biological-process annotation. Proposed replacements: pyroptotic cell death Supporting Evidence: file:human/GSDME/GSDME-source-evidence.json
GO:0012501 programmed cell death	IMP PMID:26236191 The deafness gene DFNA5 induces programmed cell death throug...	TOO GENERAL	Reason: Retain the mutant-associated death result; programmed cell death is broader than the existing pyroptotic-cell-death annotation. This replacement reflects the established effector function without reclassifying the original mutant assay as pyroptosis. Proposed replacements: pyroptotic cell death Supporting Evidence: PMID:26236191 file:human/GSDME/GSDME-source-evidence.json
GO:0016020 membrane	IBA GO_REF:0000033	ACCEPT	Reason: The inherited is_active_in membrane assertion concerns the site of activity. The cleaved human N-terminal fragment associates with membranes and causes lytic death in 293T reconstitution. Supporting Evidence: GO_REF:0000033 PMID:28045099
GO:0016020 membrane	IDA PMID:28045099 Cleavage of DFNA5 by caspase-3 during apoptosis mediates pro...	TOO GENERAL	Reason: Membrane fractionation is broad; plasma membrane is a supported specific location for the active fragment, already captured by the same study. Proposed replacements: plasma membrane Supporting Evidence: PMID:28045099
GO:0022829 wide pore channel activity	IBA GO_REF:0000033	ACCEPT	Reason: PTN002689666 (AN3) lies on the verified O60443 lineage; the literal IBD cites O60443 itself, whose experimental evidence legitimately grounds this inheritance. Cleaved human GSDME produces pores in liposome assays. Retain the established wide-pore assertion; the current definition's propanediol wording needs ontology clarification. Supporting Evidence: GO_REF:0000033 PMID:28459430
GO:0022829 wide pore channel activity	IDA PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL protea...	ACCEPT	Reason: Infected human epithelial cells cleave GSDME, and its loss reduces lysis; retain the curator's pore annotation and pyroptotic-response extension. Supporting Evidence: PMID:35594856
GO:0043410 positive regulation of MAPK cascade	IMP PMID:26236191 The deafness gene DFNA5 induces programmed cell death throug...	MARK AS OVER ANNOTATED	Reason: Mutant-expressing HEK293T cells activate JNK/ERK, and inhibition partly rescues viability. These pathological responses do not establish physiological MAPK-regulator function. Supporting Evidence: PMID:26236191 Activation of the MAPK pathway by mutDFNA5.
GO:0055085 transmembrane transport	IEA GO_REF:0000108	ACCEPT	Reason: The pore provides a physical route across membranes, making transmembrane transport part of its core effector function. Supporting Evidence: UniProtKB:O60443
GO:0070269 pyroptotic inflammatory response	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	TOO GENERAL	Reason: Caspase-3-cleaved GSDME drives lytic death; the specific pyroptotic-cell-death term better captures this effector role. Proposed replacements: pyroptotic cell death Supporting Evidence: PMID:28459430
GO:0070269 pyroptotic inflammatory response	IDA PMID:35594856 Human NLRP1 is a sensor of pathogenic coronavirus 3CL protea...	TOO GENERAL	Reason: GSDME cleavage and knockout-sensitive lysis in infected human lung cells support the narrower pyroptotic-cell-death term. Proposed replacements: pyroptotic cell death Supporting Evidence: PMID:35594856
GO:0070269 pyroptotic inflammatory response	IEA GO_REF:0000107	TOO GENERAL	Reason: The same-relation GO:0141201 annotation is a verified is_a child of this broader process. Proposed replacements: pyroptotic cell death Supporting Evidence: file:human/GSDME/GSDME-source-evidence.json
GO:0071356 cellular response to tumor necrosis factor	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	KEEP AS NON CORE	Reason: TNF plus cycloheximide triggers caspase-dependent GSDME cleavage and lysis in HeLa cells; retain this stimulus-specific context. Supporting Evidence: PMID:28459430
GO:0098586 cellular response to virus	IDA PMID:28045099 Cleavage of DFNA5 by caspase-3 during apoptosis mediates pro...	KEEP AS NON CORE	Reason: Virus infection induces cleavage and lysis in human GSDME-expressing 293T cells. The endogenous knockout experiments use mouse macrophages. Supporting Evidence: PMID:28045099
GO:0098586 cellular response to virus	IEA GO_REF:0000107	KEEP AS NON CORE	Reason: Mouse virus-response perturbations support this transfer; retain the stimulus-specific context as non-core. Supporting Evidence: PMID:28045099
GO:0141201 pyroptotic cell death	IBA GO_REF:0000033	ACCEPT	Reason: The same ancestral node supports pyroptotic cell death, and the target has no recorded branch-specific loss in the retained PAINT data. Endogenous GSDME contributes to lytic death in human airway-cell SARS-CoV-2 models. This preserves activity of the processed product, without extending it to every splice isoform. Supporting Evidence: GO_REF:0000033 PMID:35594856 UniProtKB:O60443
GO:1901612 cardiolipin binding	IDA PMID:28459430 Chemotherapy drugs induce pyroptosis through caspase-3 cleav...	ACCEPT	Reason: Accept the curator's annotation and conserved lipid-binding function; inspected cardiolipin panels use mouse/zebrafish, so independent human-assay verification remains incomplete. Supporting Evidence: PMID:28459430
GO:1901612 cardiolipin binding	IEA GO_REF:0000107	ACCEPT	Reason: Mouse Gsdme has direct cardiolipin-binding evidence, providing experimental grounding for this orthologous transfer; human-assay provenance remains separately uncertain. Supporting Evidence: PMID:28459430
GO:2001244 positive regulation of intrinsic apoptotic signaling pathway	IDA PMID:21522185 The DFNA5 gene, responsible for hearing loss and involved in...	ACCEPT	Reason: The earlier apoptosis study lacks a direct mitochondrial mechanism; later human-cell knockout/rescue and organelle assays establish GSDME-mediated cytochrome-c release and amplification. Supporting Evidence: PMID:21522185 PMID:30976076 releasing cytochrome c and activating the apoptosome