{"gene":"GSDMA","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2022,"finding":"The GAS cysteine protease SpeB cleaves GSDMA after Gln246, releasing an active N-terminal fragment that inserts into membranes and triggers keratinocyte pyroptosis. GSDMA thus acts as both a direct sensor and substrate of SpeB virulence activity.","method":"In vitro cleavage assay, site-directed mutagenesis (Gln246 cleavage site), genetic knockout mice (Gsdma1-deficient) showing uncontrolled GAS dissemination, cell death assays in keratinocytes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — two independent labs (PMID:35110732 and PMID:35545676) simultaneously reported the same SpeB-GSDMA cleavage mechanism using in vitro cleavage assays, mutagenesis, and genetic knockout models","pmids":["35110732","35545676"],"is_preprint":false},{"year":2022,"finding":"SpeB cleavage of GSDMA releases an active amino-terminal fragment that inserts into membranes to form lytic pores, demonstrating that GSDMs can act independently of host caspase regulators as direct sensors of exogenous bacterial proteases.","method":"Biochemical membrane permeabilization assays, GAS infection of keratinocytes with SpeB-expressing strains, triple Gsdma knockout mice showing increased susceptibility to M1T1 GAS infection","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — replicated independently in two concurrent Nature papers using complementary in vitro and in vivo methods","pmids":["35545676","35110732"],"is_preprint":false},{"year":2013,"finding":"Mouse Gsdma is expressed specifically in the inner root sheath of hair follicles and suprabasal cell layers; overexpression of wild-type Gsdma or a point mutant (Ala339Thr) causes epidermal hyperplasia, indicating GSDMA regulates epithelial maintenance and homeostasis.","method":"Gsdma knockout mice (no visible phenotype), transgenic overexpression mice, histological analysis of skin phenotype","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization and gain-of-function transgenic experiments with clear phenotypic readout, single lab","pmids":["23979942"],"is_preprint":false},{"year":2009,"finding":"GSDMA (GSDM) has cell-growth inhibition activity in gastric cancer cells, as demonstrated by colony formation assay; GSDMB, which is closely related to GSDMA, lacks this activity, indicating functional divergence among family members.","method":"Colony formation assay in gastric cancer cells transfected with GSDM family members","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single functional assay, but direct loss/gain-of-function readout","pmids":["19051310"],"is_preprint":false},{"year":2023,"finding":"FAM111B (a trypsin-domain protease) binds to GSDMA and promotes its degradation; the trypsin protease domain of FAM111B is essential for this activity and for promoting esophageal cancer progression and cisplatin resistance.","method":"Co-IP/binding assays, Western blot, siRNA knockdown, xenograft assays, RNA-seq","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — binding interaction demonstrated with Co-IP, functional consequences shown in cell and xenograft models, single lab","pmids":["37672204"],"is_preprint":false},{"year":2026,"finding":"GSDMA is S-acylated at conserved cysteine residues in its N-terminal domain; this modification promotes pyroptosis by facilitating membrane anchoring and protein oligomerization. Recombinant GSDMA can undergo S-acylation in vitro via direct interaction with palmitoyl-CoA independent of palmitoyl transferases. ABHD17A was identified as a deacylase that removes this modification and regulates the dynamic S-acylation cycle of GSDMA.","method":"In vitro S-acylation assays with recombinant protein and palmitoyl-CoA, mutagenesis of cysteine residues, membrane anchoring assays, oligomerization assays, siRNA knockdown of ABHD17A, pyroptosis readouts","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins, mutagenesis, and multiple orthogonal functional readouts; confirmed in peer-reviewed publication (PMID:41972293) supported by preprint versions","pmids":["41972293","41279037"],"is_preprint":false},{"year":2026,"finding":"RBM47 directly binds to the 3'-UTR of GSDMA mRNA and stabilizes it, increasing GSDMA protein expression. GSDMA is required downstream of RBM47 for mesenchymal-to-epithelial transition (MET), suppression of CRC cell migration and invasion, and induction of pyroptosis. Knockdown of GSDMA abolishes RBM47-mediated pyroptosis and chemosensitization to Oxaliplatin.","method":"RNA-Seq, RBM47 KD/OE, GSDMA KD rescue experiments, migration/invasion assays, pyroptosis assays (cell swelling, membrane rupture), drug sensitivity assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-binding demonstrated, epistasis established by GSDMA knockdown rescue, multiple functional readouts, single lab","pmids":["41681975"],"is_preprint":false},{"year":2017,"finding":"DNA methylation at the GSDMA promoter represses GSDMA expression; treatment with the DNA methyltransferase inhibitor 5-aza-dC (causing demethylation) upregulates GSDMA expression in multiple epithelial cell lines, accompanied by a measurable decrease in promoter methylation.","method":"5-aza-dC treatment of NuLi-1, 293T, and MCF-7 cell lines, RT-PCR, promoter methylation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological demethylation with promoter methylation measurement, replicated across three cell lines, single lab","pmids":["28241063"],"is_preprint":false}],"current_model":"GSDMA is a pore-forming gasdermin predominantly expressed in skin keratinocytes that is activated by proteolytic cleavage (notably by the GAS cysteine protease SpeB at Gln246), releasing an N-terminal fragment that oligomerizes, anchors to membranes via S-acylation at conserved cysteine residues (facilitated by palmitoyl-CoA and reversed by ABHD17A), and forms lytic pores to execute pyroptosis; its expression is regulated by promoter DNA methylation and mRNA stabilization by RBM47, while FAM111B can degrade GSDMA protein to suppress its tumor-suppressive and pyroptotic activities."},"narrative":{"mechanistic_narrative":"GSDMA is a pore-forming gasdermin that executes pyroptosis in epithelial cells, most prominently keratinocytes, where it functions as a direct sensor of bacterial virulence proteases [PMID:35110732, PMID:35545676]. The group A Streptococcus cysteine protease SpeB cleaves GSDMA after Gln246, liberating an N-terminal fragment that inserts into membranes to form lytic pores; this allows GSDMA to trigger keratinocyte death independently of host caspases, and Gsdma-deficient mice show uncontrolled GAS dissemination [PMID:35110732, PMID:35545676]. Membrane engagement of the N-terminal fragment is reinforced by S-acylation at conserved N-terminal cysteines, a modification that promotes membrane anchoring and oligomerization, can occur directly through palmitoyl-CoA without a palmitoyltransferase, and is reversed by the deacylase ABHD17A, which thereby sets a dynamic S-acylation cycle controlling pore formation [PMID:41972293, PMID:41279037]. Beyond host defense, GSDMA acts as a growth-suppressive and pyroptosis-inducing factor in epithelial tumors: it inhibits gastric cancer cell colony formation [PMID:19051310], is required downstream of the RNA-binding protein RBM47 for mesenchymal-to-epithelial transition, suppression of colorectal cancer migration/invasion, and chemosensitization [PMID:41681975], and is antagonized by FAM111B, whose trypsin protease domain binds and degrades GSDMA to promote esophageal cancer progression and cisplatin resistance [PMID:37672204]. GSDMA expression is set transcriptionally by promoter DNA methylation [PMID:28241063] and post-transcriptionally by RBM47-mediated mRNA stabilization [PMID:41681975], and the protein contributes to epidermal homeostasis, since its overexpression in mouse skin causes epidermal hyperplasia [PMID:23979942].","teleology":[{"year":2009,"claim":"Established GSDMA as a functionally active, growth-suppressive member of the gasdermin family rather than an inert paralog, distinguishing it from the closely related GSDMB.","evidence":"Colony formation assay in gastric cancer cells transfected with GSDM family members","pmids":["19051310"],"confidence":"Medium","gaps":["Did not define the molecular mechanism of growth inhibition","No connection yet to pore formation or pyroptosis","Single assay in one cancer cell context"]},{"year":2013,"claim":"Localized GSDMA expression to hair follicle inner root sheath and suprabasal keratinocytes and linked it to epithelial maintenance, showing gain-of-function causes epidermal hyperplasia while loss-of-function is phenotypically silent.","evidence":"Gsdma knockout and transgenic overexpression mice with skin histology","pmids":["23979942"],"confidence":"Medium","gaps":["Mechanism linking GSDMA to hyperplasia not defined","No activating protease or cleavage event identified","Redundancy among mouse Gsdma paralogs unresolved"]},{"year":2017,"claim":"Identified a transcriptional control point for GSDMA, showing that promoter DNA methylation represses its expression and that demethylation restores it across epithelial cell lines.","evidence":"5-aza-dC treatment with RT-PCR and promoter methylation assays in NuLi-1, 293T, MCF-7","pmids":["28241063"],"confidence":"Medium","gaps":["Did not identify the methyltransferases or physiological signals controlling methylation","No link to downstream functional consequence"]},{"year":2022,"claim":"Defined GSDMA's core mechanism: it is a direct sensor and substrate of the GAS protease SpeB, which cleaves after Gln246 to release an N-terminal fragment that forms lytic membrane pores and drives keratinocyte pyroptosis as an anti-bacterial defense.","evidence":"In vitro cleavage and membrane permeabilization assays, Gln246 mutagenesis, and Gsdma knockout mice with GAS infection, replicated in two concurrent Nature papers","pmids":["35110732","35545676"],"confidence":"High","gaps":["Did not resolve how the cleaved fragment anchors to and oligomerizes in membranes","Endogenous host proteases activating GSDMA not defined","Structure of the GSDMA pore not determined"]},{"year":2023,"claim":"Revealed a degradative regulatory mechanism, showing FAM111B binds GSDMA and degrades it via its trypsin protease domain to suppress GSDMA's tumor-suppressive activity and promote cancer progression.","evidence":"Co-IP/binding assays, Western blot, siRNA knockdown, and xenografts in esophageal cancer models","pmids":["37672204"],"confidence":"Medium","gaps":["Direct proteolysis of GSDMA by FAM111B not shown biochemically","Cleavage site/products undefined","Single-lab cancer-model evidence"]},{"year":2026,"claim":"Defined the membrane-targeting step of GSDMA pore formation, showing S-acylation of conserved N-terminal cysteines promotes anchoring and oligomerization via direct palmitoyl-CoA reaction and is reversed by the deacylase ABHD17A.","evidence":"In vitro S-acylation reconstitution with recombinant protein and palmitoyl-CoA, cysteine mutagenesis, membrane/oligomerization assays, and ABHD17A knockdown","pmids":["41972293","41279037"],"confidence":"High","gaps":["Physiological enzymes/signals controlling the acylation cycle in vivo not established","Stoichiometry/structure of the acylated oligomer undefined"]},{"year":2026,"claim":"Established a post-transcriptional activation axis, showing RBM47 binds the GSDMA 3'-UTR to stabilize its mRNA, and that GSDMA is required downstream for mesenchymal-to-epithelial transition, suppression of CRC invasion, pyroptosis, and chemosensitization.","evidence":"RNA-Seq, RBM47 knockdown/overexpression with GSDMA knockdown rescue, migration/invasion, pyroptosis, and oxaliplatin sensitivity assays","pmids":["41681975"],"confidence":"Medium","gaps":["Protease activating GSDMA in this CRC context not identified","Direct binding site on the 3'-UTR not mapped at nucleotide resolution","Single-lab epistasis evidence"]},{"year":null,"claim":"The endogenous host proteases that activate GSDMA in human epithelial homeostasis and tumor suppression, and the high-resolution structure of the assembled GSDMA pore, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No host activating protease characterized outside bacterial SpeB","No structural model of the GSDMA pore","In vivo physiological triggers of the S-acylation cycle unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,5]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["FAM111B","RBM47","ABHD17A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QA5","full_name":"Gasdermin-A","aliases":["Gasdermin-1"],"length_aa":445,"mass_kda":49.4,"function":"This form constitutes the precursor of the pore-forming protein and acts as a sensor of infection: upon infection by S.pyogenes, specifically cleaved by S.pyogenes effector protein SpeB in epithelial cells, releasing the N-terminal moiety (Gasdermin-A, N-terminal) that binds to membranes and forms pores, triggering pyroptosis Pore-forming protein that causes membrane permeabilization and pyroptosis (PubMed:17471240, PubMed:27281216, PubMed:35110732, PubMed:35545676). Released upon cleavage by S.pyogenes effector protein SpeB, and binds to membrane inner leaflet lipids (PubMed:27281216, PubMed:35110732, PubMed:35545676). Homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:27281216, PubMed:35110732, PubMed:35545676). Pyroptosis triggers the elimination of the infected skin cell, depriving the pathogen of its protective niche, while inducing an inflammatory response (PubMed:35110732, PubMed:35545676). This ultimately prevents bacterial penetration of the epithelial barrier and a subsequent systemic dissemination of the pathogen (PubMed:35110732, PubMed:35545676). Binds to cardiolipin and other acidic phospholipids, such as phosphatidylserine, which mediate its targeting to the inner leaflet membrane (PubMed:27281216, PubMed:35110732)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96QA5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GSDMA","classification":"Common Essential","n_dependent_lines":281,"n_total_lines":1208,"dependency_fraction":0.2326158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/GSDMA","total_profiled":1310},"omim":[{"mim_id":"617042","title":"GASDERMIN D; GSDMD","url":"https://www.omim.org/entry/617042"},{"mim_id":"611221","title":"GASDERMIN B; GSDMB","url":"https://www.omim.org/entry/611221"},{"mim_id":"611218","title":"GASDERMIN A; GSDMA","url":"https://www.omim.org/entry/611218"},{"mim_id":"610219","title":"PEJVAKIN; PJVK","url":"https://www.omim.org/entry/610219"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":58.0}],"url":"https://www.proteinatlas.org/search/GSDMA"},"hgnc":{"alias_symbol":["FLJ39120"],"prev_symbol":["GSDM","GSDM1"]},"alphafold":{"accession":"Q96QA5","domains":[{"cath_id":"-","chopping":"3-66_83-220","consensus_level":"high","plddt":81.209,"start":3,"end":220},{"cath_id":"-","chopping":"258-445","consensus_level":"high","plddt":86.7922,"start":258,"end":445}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QA5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QA5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QA5-F1-predicted_aligned_error_v6.png","plddt_mean":79.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GSDMA","jax_strain_url":"https://www.jax.org/strain/search?query=GSDMA"},"sequence":{"accession":"Q96QA5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QA5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QA5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QA5"}},"corpus_meta":[{"pmid":"35110732","id":"PMC_35110732","title":"Streptococcal 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significantly suppressed in human gastric cancer cells.","date":"2000","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/10967128","citation_count":195,"is_preprint":false},{"pmid":"35545676","id":"PMC_35545676","title":"Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35545676","citation_count":152,"is_preprint":false},{"pmid":"15010812","id":"PMC_15010812","title":"Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15010812","citation_count":83,"is_preprint":false},{"pmid":"28314753","id":"PMC_28314753","title":"Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic 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GSDMA thus acts as both a direct sensor and substrate of SpeB virulence activity.\",\n      \"method\": \"In vitro cleavage assay, site-directed mutagenesis (Gln246 cleavage site), genetic knockout mice (Gsdma1-deficient) showing uncontrolled GAS dissemination, cell death assays in keratinocytes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — two independent labs (PMID:35110732 and PMID:35545676) simultaneously reported the same SpeB-GSDMA cleavage mechanism using in vitro cleavage assays, mutagenesis, and genetic knockout models\",\n      \"pmids\": [\"35110732\", \"35545676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SpeB cleavage of GSDMA releases an active amino-terminal fragment that inserts into membranes to form lytic pores, demonstrating that GSDMs can act independently of host caspase regulators as direct sensors of exogenous bacterial proteases.\",\n      \"method\": \"Biochemical membrane permeabilization assays, GAS infection of keratinocytes with SpeB-expressing strains, triple Gsdma knockout mice showing increased susceptibility to M1T1 GAS infection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — replicated independently in two concurrent Nature papers using complementary in vitro and in vivo methods\",\n      \"pmids\": [\"35545676\", \"35110732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mouse Gsdma is expressed specifically in the inner root sheath of hair follicles and suprabasal cell layers; overexpression of wild-type Gsdma or a point mutant (Ala339Thr) causes epidermal hyperplasia, indicating GSDMA regulates epithelial maintenance and homeostasis.\",\n      \"method\": \"Gsdma knockout mice (no visible phenotype), transgenic overexpression mice, histological analysis of skin phenotype\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and gain-of-function transgenic experiments with clear phenotypic readout, single lab\",\n      \"pmids\": [\"23979942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GSDMA (GSDM) has cell-growth inhibition activity in gastric cancer cells, as demonstrated by colony formation assay; GSDMB, which is closely related to GSDMA, lacks this activity, indicating functional divergence among family members.\",\n      \"method\": \"Colony formation assay in gastric cancer cells transfected with GSDM family members\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single functional assay, but direct loss/gain-of-function readout\",\n      \"pmids\": [\"19051310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM111B (a trypsin-domain protease) binds to GSDMA and promotes its degradation; the trypsin protease domain of FAM111B is essential for this activity and for promoting esophageal cancer progression and cisplatin resistance.\",\n      \"method\": \"Co-IP/binding assays, Western blot, siRNA knockdown, xenograft assays, RNA-seq\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — binding interaction demonstrated with Co-IP, functional consequences shown in cell and xenograft models, single lab\",\n      \"pmids\": [\"37672204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GSDMA is S-acylated at conserved cysteine residues in its N-terminal domain; this modification promotes pyroptosis by facilitating membrane anchoring and protein oligomerization. Recombinant GSDMA can undergo S-acylation in vitro via direct interaction with palmitoyl-CoA independent of palmitoyl transferases. ABHD17A was identified as a deacylase that removes this modification and regulates the dynamic S-acylation cycle of GSDMA.\",\n      \"method\": \"In vitro S-acylation assays with recombinant protein and palmitoyl-CoA, mutagenesis of cysteine residues, membrane anchoring assays, oligomerization assays, siRNA knockdown of ABHD17A, pyroptosis readouts\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins, mutagenesis, and multiple orthogonal functional readouts; confirmed in peer-reviewed publication (PMID:41972293) supported by preprint versions\",\n      \"pmids\": [\"41972293\", \"41279037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM47 directly binds to the 3'-UTR of GSDMA mRNA and stabilizes it, increasing GSDMA protein expression. GSDMA is required downstream of RBM47 for mesenchymal-to-epithelial transition (MET), suppression of CRC cell migration and invasion, and induction of pyroptosis. Knockdown of GSDMA abolishes RBM47-mediated pyroptosis and chemosensitization to Oxaliplatin.\",\n      \"method\": \"RNA-Seq, RBM47 KD/OE, GSDMA KD rescue experiments, migration/invasion assays, pyroptosis assays (cell swelling, membrane rupture), drug sensitivity assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-binding demonstrated, epistasis established by GSDMA knockdown rescue, multiple functional readouts, single lab\",\n      \"pmids\": [\"41681975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DNA methylation at the GSDMA promoter represses GSDMA expression; treatment with the DNA methyltransferase inhibitor 5-aza-dC (causing demethylation) upregulates GSDMA expression in multiple epithelial cell lines, accompanied by a measurable decrease in promoter methylation.\",\n      \"method\": \"5-aza-dC treatment of NuLi-1, 293T, and MCF-7 cell lines, RT-PCR, promoter methylation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological demethylation with promoter methylation measurement, replicated across three cell lines, single lab\",\n      \"pmids\": [\"28241063\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GSDMA is a pore-forming gasdermin predominantly expressed in skin keratinocytes that is activated by proteolytic cleavage (notably by the GAS cysteine protease SpeB at Gln246), releasing an N-terminal fragment that oligomerizes, anchors to membranes via S-acylation at conserved cysteine residues (facilitated by palmitoyl-CoA and reversed by ABHD17A), and forms lytic pores to execute pyroptosis; its expression is regulated by promoter DNA methylation and mRNA stabilization by RBM47, while FAM111B can degrade GSDMA protein to suppress its tumor-suppressive and pyroptotic activities.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GSDMA is a pore-forming gasdermin that executes pyroptosis in epithelial cells, most prominently keratinocytes, where it functions as a direct sensor of bacterial virulence proteases [#0, #1]. The group A Streptococcus cysteine protease SpeB cleaves GSDMA after Gln246, liberating an N-terminal fragment that inserts into membranes to form lytic pores; this allows GSDMA to trigger keratinocyte death independently of host caspases, and Gsdma-deficient mice show uncontrolled GAS dissemination [#0, #1]. Membrane engagement of the N-terminal fragment is reinforced by S-acylation at conserved N-terminal cysteines, a modification that promotes membrane anchoring and oligomerization, can occur directly through palmitoyl-CoA without a palmitoyltransferase, and is reversed by the deacylase ABHD17A, which thereby sets a dynamic S-acylation cycle controlling pore formation [#5]. Beyond host defense, GSDMA acts as a growth-suppressive and pyroptosis-inducing factor in epithelial tumors: it inhibits gastric cancer cell colony formation [#3], is required downstream of the RNA-binding protein RBM47 for mesenchymal-to-epithelial transition, suppression of colorectal cancer migration/invasion, and chemosensitization [#6], and is antagonized by FAM111B, whose trypsin protease domain binds and degrades GSDMA to promote esophageal cancer progression and cisplatin resistance [#4]. GSDMA expression is set transcriptionally by promoter DNA methylation [#7] and post-transcriptionally by RBM47-mediated mRNA stabilization [#6], and the protein contributes to epidermal homeostasis, since its overexpression in mouse skin causes epidermal hyperplasia [#2].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established GSDMA as a functionally active, growth-suppressive member of the gasdermin family rather than an inert paralog, distinguishing it from the closely related GSDMB.\",\n      \"evidence\": \"Colony formation assay in gastric cancer cells transfected with GSDM family members\",\n      \"pmids\": [\"19051310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular mechanism of growth inhibition\", \"No connection yet to pore formation or pyroptosis\", \"Single assay in one cancer cell context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Localized GSDMA expression to hair follicle inner root sheath and suprabasal keratinocytes and linked it to epithelial maintenance, showing gain-of-function causes epidermal hyperplasia while loss-of-function is phenotypically silent.\",\n      \"evidence\": \"Gsdma knockout and transgenic overexpression mice with skin histology\",\n      \"pmids\": [\"23979942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GSDMA to hyperplasia not defined\", \"No activating protease or cleavage event identified\", \"Redundancy among mouse Gsdma paralogs unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a transcriptional control point for GSDMA, showing that promoter DNA methylation represses its expression and that demethylation restores it across epithelial cell lines.\",\n      \"evidence\": \"5-aza-dC treatment with RT-PCR and promoter methylation assays in NuLi-1, 293T, MCF-7\",\n      \"pmids\": [\"28241063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the methyltransferases or physiological signals controlling methylation\", \"No link to downstream functional consequence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined GSDMA's core mechanism: it is a direct sensor and substrate of the GAS protease SpeB, which cleaves after Gln246 to release an N-terminal fragment that forms lytic membrane pores and drives keratinocyte pyroptosis as an anti-bacterial defense.\",\n      \"evidence\": \"In vitro cleavage and membrane permeabilization assays, Gln246 mutagenesis, and Gsdma knockout mice with GAS infection, replicated in two concurrent Nature papers\",\n      \"pmids\": [\"35110732\", \"35545676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the cleaved fragment anchors to and oligomerizes in membranes\", \"Endogenous host proteases activating GSDMA not defined\", \"Structure of the GSDMA pore not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a degradative regulatory mechanism, showing FAM111B binds GSDMA and degrades it via its trypsin protease domain to suppress GSDMA's tumor-suppressive activity and promote cancer progression.\",\n      \"evidence\": \"Co-IP/binding assays, Western blot, siRNA knockdown, and xenografts in esophageal cancer models\",\n      \"pmids\": [\"37672204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteolysis of GSDMA by FAM111B not shown biochemically\", \"Cleavage site/products undefined\", \"Single-lab cancer-model evidence\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the membrane-targeting step of GSDMA pore formation, showing S-acylation of conserved N-terminal cysteines promotes anchoring and oligomerization via direct palmitoyl-CoA reaction and is reversed by the deacylase ABHD17A.\",\n      \"evidence\": \"In vitro S-acylation reconstitution with recombinant protein and palmitoyl-CoA, cysteine mutagenesis, membrane/oligomerization assays, and ABHD17A knockdown\",\n      \"pmids\": [\"41972293\", \"41279037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological enzymes/signals controlling the acylation cycle in vivo not established\", \"Stoichiometry/structure of the acylated oligomer undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a post-transcriptional activation axis, showing RBM47 binds the GSDMA 3'-UTR to stabilize its mRNA, and that GSDMA is required downstream for mesenchymal-to-epithelial transition, suppression of CRC invasion, pyroptosis, and chemosensitization.\",\n      \"evidence\": \"RNA-Seq, RBM47 knockdown/overexpression with GSDMA knockdown rescue, migration/invasion, pyroptosis, and oxaliplatin sensitivity assays\",\n      \"pmids\": [\"41681975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease activating GSDMA in this CRC context not identified\", \"Direct binding site on the 3'-UTR not mapped at nucleotide resolution\", \"Single-lab epistasis evidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous host proteases that activate GSDMA in human epithelial homeostasis and tumor suppression, and the high-resolution structure of the assembled GSDMA pore, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No host activating protease characterized outside bacterial SpeB\", \"No structural model of the GSDMA pore\", \"In vivo physiological triggers of the S-acylation cycle unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FAM111B\", \"RBM47\", \"ABHD17A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}