{"gene":"GSDMB","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2020,"finding":"Granzyme A (GZMA) from cytotoxic lymphocytes directly cleaves GSDMB, unleashing its pore-forming activity and triggering pyroptosis in target cells. NK cells and cytotoxic T lymphocytes kill GSDMB-positive cells through this mechanism. IFN-γ upregulates GSDMB expression and promotes pyroptosis. Introducing GZMA-cleavable GSDMB into mouse cancer cells promotes tumor clearance in vivo.","method":"In vitro cleavage assays, cell death assays, NK/CTL co-culture killing assays, mouse tumor models, IFN-γ treatment experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro cleavage, cell killing assays, mutagenesis, in vivo models), replicated by multiple subsequent studies","pmids":["32299851"],"is_preprint":false},{"year":2023,"finding":"Crystal structure of IpaH7.8-GSDMB complex reveals how the Shigella flexneri ubiquitin-ligase effector IpaH7.8 recognizes the GSDMB pore-forming domain and ubiquitinates it for proteasomal degradation. Full-length GSDMB crystal structure shows stronger autoinhibition than other gasdermins. Presence of exon 6 in GSDMB isoforms dictates pore-forming/pyroptotic activity. Cryo-EM structure of the 27-fold-symmetric GSDMB pore reveals conformational changes driving pore formation and an essential role for exon-6-derived elements in pore assembly.","method":"X-ray crystallography (IpaH7.8-GSDMB complex and full-length GSDMB), cryo-EM (GSDMB pore), biochemical ubiquitination assays, isoform pyroptosis assays, mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + cryo-EM structure + mutagenesis + functional assays in a single rigorous study","pmids":["36991125"],"is_preprint":false},{"year":2021,"finding":"The Shigella flexneri effector IpaH7.8 ubiquitinates GSDMB and targets it for 26S proteasome-dependent destruction, protecting Shigella from NK cell bactericidal killing. GSDMB exhibits direct microbiocidal activity through recognition of phospholipids found on Gram-negative bacterial membranes, killing bacteria directly rather than by lysing host cells.","method":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, NK cell killing assays, bacterial membrane lipid-binding assays, GSDMB knockdown/overexpression","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional killing assays, lipid-binding experiments, genetic knockdown with defined phenotypic readouts; replicated structurally by subsequent papers","pmids":["34022140"],"is_preprint":false},{"year":2022,"finding":"GSDMB promotes epithelial restitution and repair independent of pyroptosis in inflamed colonocytes. GSDMB-deficient epithelial cells show hyper-adhesiveness, enhanced formation of vinculin-based focal adhesions, and arrest in wound closure. This is dependent on PDGF-A-mediated FAK phosphorylation. Disease-associated GSDMB SNPs disrupt epithelial restitution/repair.","method":"GSDMB knockout/knockdown in epithelial cells and organoids, in vitro wound closure assays, transcriptome profiling, focal adhesion analysis, FAK phosphorylation assays, single-cell analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype, multiple orthogonal assays (wound closure, focal adhesion, phosphorylation, transcriptomics), single lab","pmids":["35021065"],"is_preprint":false},{"year":2019,"finding":"GSDMB directly binds the CARD domain of caspase-4, promoting caspase-4 activity, which is required for cleavage of GSDMD in non-canonical pyroptosis. Downregulation of GSDMB alleviates GSDMD cleavage and cell death; overexpression promotes GSDMD cleavage and LDH release.","method":"Co-immunoprecipitation (GSDMB-caspase-4 CARD domain binding), caspase activity assays, GSDMB knockdown/overexpression, LDH release assays, Western blot for GSDMD cleavage","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for binding, functional assays for caspase-4 activity and GSDMD cleavage, single lab with multiple methods","pmids":["30321352"],"is_preprint":false},{"year":2016,"finding":"GSDMB overexpression in primary human bronchial epithelium increases expression of TGF-β1 and 5-lipoxygenase (5-LO). GSDMB induces TGF-β1 expression via induction of 5-LO, as knockdown of 5-LO in GSDMB-overexpressing cells inhibited TGF-β1 expression. Transgenic mice expressing human GSDMB show spontaneous airway hyperresponsiveness and remodeling without inflammation.","method":"Overexpression in primary human bronchial epithelium, siRNA knockdown of 5-LO, transgenic mouse model (hGSDMBZp3-Cre), gene expression assays","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via siRNA knockdown, in vitro and in vivo models, single lab with multiple orthogonal approaches","pmids":["27799535"],"is_preprint":false},{"year":2023,"finding":"GSDMB splicing isoforms are functionally distinct: isoforms 3 and 4 (containing exon 6) cause pyroptosis after GZMA cleavage, while isoforms 1, 2, and 5 (lacking intact exon 6) do not. Non-cytotoxic GSDMB N-terminal fragments block pyroptosis caused by cytotoxic isoforms in a dominant-negative manner. Upon NK cell attack, different isoforms lead to distinct cell death modes (pyroptosis, mixed pyroptosis/apoptosis, or apoptosis only).","method":"Isoform expression and GZMA cleavage assays, NK cell killing assays, cell death phenotype analysis (pyroptosis vs apoptosis markers), dominant-negative experiments, structural analysis of belt motif","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple isoforms tested with functional assays, NK cell killing experiments, dominant-negative validation, consistent with structural data from other labs","pmids":["37115914"],"is_preprint":false},{"year":2023,"finding":"Exon 6 translation is essential for GSDMB-mediated pyroptosis; GSDMB isoforms lacking exon 6 (GSDMB1-2) cannot cause cancer cell death. GSDMB N-terminal constructs containing exon 6 provoke cell membrane lysis and concomitant mitochondrial damage. Specific residues within exon 6 and other N-terminal domain regions are important for GSDMB-triggered cell death and mitochondrial impairment. Neutrophil elastase and caspase cleavage of GSDMB produces short N-terminal fragments with no cytotoxic activity, suggesting these proteases act as inhibitory mechanisms of pyroptosis.","method":"Isoform expression and cell death assays, mutagenesis of specific residues, mitochondrial damage assays, protease cleavage assays (GZMA, neutrophil elastase, caspases), cell membrane lysis assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution of cleavage by multiple proteases, mutagenesis of functional residues, multiple orthogonal death assays, single lab","pmids":["36899106"],"is_preprint":false},{"year":2023,"finding":"Crystal structure of GSDMB in complex with IpaH7.8 identifies membrane engagement sites of GSDMB. Structural analysis reveals how IpaH7.8 interacts with GSDMB and ubiquitinates it. Two residues in the α1-α2 loop of mouse GSDMD make it invulnerable to IpaH7.8-mediated degradation (non-identical to human).","method":"X-ray crystallography (GSDMB-IpaH7.8 complex), biochemical ubiquitination assays, mutagenesis of α1-α2 loop residues, functional degradation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis and biochemical validation, single lab but multiple orthogonal methods","pmids":["36599845"],"is_preprint":false},{"year":2023,"finding":"Caspase-7 cleaves GSDMB at the D91 site during apoptosis, generating a C-terminal fragment (92–417 aa) that binds back to the GSDMB N-terminus (1–91 aa) to block GSDMB's pro-pyroptotic function, thereby inhibiting non-canonical pyroptosis. The GSDMB N-domain (1–91 aa) is important for binding caspase-4 and promoting non-canonical pyroptosis. During bacterial infection (E. coli, S. Typhimurium) and in a septic mouse model, inhibition of caspase-7/GSDMB axis increased pyroptotic cell death.","method":"Caspase-7 cleavage assays, co-immunoprecipitation (GSDMB-C binding GSDMB-N, GSDMB binding caspase-4), cell death assays with bacterial infection models, caspase-7 inhibitor and knockout mouse experiments","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cleavage site identified with functional consequence, Co-IP of auto-inhibitory interaction, in vivo mouse model, single lab","pmids":["37591921"],"is_preprint":false},{"year":2021,"finding":"GSDMB interacts with STAT3 to increase STAT3 phosphorylation and modulate glucose metabolism in bladder cancer cells. USP24 (a deubiquitinase) stabilizes GSDMB by preventing its degradation, activating downstream STAT3 signaling. This USP24/GSDMB/STAT3 axis promotes bladder cancer growth.","method":"Mass spectrometry and co-immunoprecipitation (GSDMB-STAT3 and GSDMB-USP24 interactions), GSDMB overexpression/knockdown, STAT3 phosphorylation assays, USP24 inhibitor treatment, xenograft tumor models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus MS for interactions, functional assays, in vivo xenograft, single lab","pmids":["34326684"],"is_preprint":false},{"year":2024,"finding":"GSDMB interacts with the C-terminus of STING and promotes translocation of STING to the Golgi, leading to phosphorylation of IRF3 and induction of interferons and interferon-stimulated genes (ISGs) via the cGAS-STING pathway in bronchial epithelial cells.","method":"Co-immunoprecipitation (GSDMB-STING interaction), immunofluorescence (STING Golgi translocation), IRF3 phosphorylation assays, GSDMB overexpression and knockout in BEAS-2B and primary bronchial epithelial cells, qPCR/ELISA for IFN/ISG expression","journal":"Journal of respiratory biology and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, localization imaging, gain- and loss-of-function with defined signaling readout, single lab","pmids":["38737375"],"is_preprint":false},{"year":2024,"finding":"4-Octyl itaconate (4-OI) inhibits GSDMB-mediated pyroptosis by directly modifying Cys54, Cys148, and Ser212 on granzyme A (GZMA), thereby blocking GZMA-mediated cleavage of GSDMB rather than acting on GSDMB itself.","method":"Mass spectrometry-based identification of 4-OI modification sites on GZMA, GZMA cleavage assays, pyroptosis assays, transgenic mouse colitis model","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification of covalent modification sites on GZMA with functional cleavage and pyroptosis assays, single lab","pmids":["38982510"],"is_preprint":false},{"year":2024,"finding":"GSDMB interacts with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which binds to and recognizes the 3'-UTR of DUSP6 mRNA, enhancing DUSP6 protein translation and inhibiting downstream ERK phosphorylation, thereby suppressing colorectal cancer cell proliferation.","method":"Co-immunoprecipitation (GSDMB-IGF2BP1), RNA-binding assays (IGF2BP1-DUSP6 3'-UTR), ERK phosphorylation assays, GSDMB transgenic mouse model, organoid experiments","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for protein interaction, mRNA binding assay, downstream signaling assay, in vivo model; single lab","pmids":["39353395"],"is_preprint":false},{"year":2026,"finding":"Human GZMA targets GSDMB via specific, high-affinity binding to the autoinhibitory GSDMB-C domain. GZMA dimerization is required for this interaction. A crystal structure of the GZMA-GSDMB-C complex shows 2:2 stoichiometry with an exosite at each of two symmetric dimer interfaces in GZMA; the exosite engages a two-loop-organized site in the GSDMB-C domain, enabling functional cleavage at Lys244. Mouse GZMA has a less efficient exosite; mutation of the mouse GZMA exosite enabled it to efficiently cleave and activate GSDMB.","method":"X-ray crystallography (GZMA-GSDMB-C complex), binding affinity measurements, GZMA dimerization analysis, mutagenesis of exosite residues, cleavage assays with mouse/human GZMA variants","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with defined stoichiometry, mutagenesis of functional exosite, biochemical cleavage assays; single lab but multiple orthogonal methods","pmids":["41592574"],"is_preprint":false},{"year":2010,"finding":"An Alu element in the 5' regulatory region upstream of GSDMB positively regulates GSDMB expression. A putative IKZF binding motif within this Alu element is crucial for upregulating GSDMB expression, as shown by reporter assays with intact, deleted, and mutated Alu elements.","method":"Reporter assays with intact, deleted, and mutated Alu element constructs; expression analysis in gastric cancer patient tissues","journal":"Genes & genetic systems","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with multiple deletion/mutation constructs identifying functional element, single lab","pmids":["20410667"],"is_preprint":false},{"year":2008,"finding":"GSDMB (GSDML) protein is localized to the cytoplasm in most cell types, but shows a distinctive vesicular staining pattern in the apical region of gastric chief cells and colonic surface mucous cells, and the basal region of neuroendocrine cells, suggesting involvement in a secretory pathway.","method":"Immunohistochemistry and immunoblotting using anti-peptide antibodies developed against GSDML; in vitro transcription-translation for antibody specificity verification","journal":"Pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by IHC without functional consequence established, single lab","pmids":["18038310"],"is_preprint":false},{"year":2008,"finding":"GFP-GSDMB (GSDML1) fusion protein localizes predominantly to the nucleus in MCF7 and HeLa cells but exclusively to the cytoplasm in HepG2 cells, indicating cell-type-dependent subcellular localization. Ectopic expression of GSDMB1 enhanced cell growth, while inhibition of its endogenous expression decreased proliferation.","method":"GFP fusion protein live cell imaging, siRNA knockdown and overexpression, BrdU incorporation assay, MTT-equivalent proliferation assays","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by GFP fusion, proliferation assays without clear pathway placement, single lab","pmids":["18633457"],"is_preprint":false},{"year":2025,"finding":"GATA1 binds to the promoter region of GSDMB and facilitates its expression. GSDMB overexpression upregulates mesenchymal markers and promotes epithelial-mesenchymal transition (EMT), as well as proliferation and migration in TGF-β1-treated bronchial epithelial cells.","method":"Chromatin immunoprecipitation (GATA1 binding to GSDMB promoter), GSDMB overexpression in Beas-2B cells with TGF-β1 treatment, EMT marker assays, proliferation and migration assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP for transcription factor binding, gain-of-function with defined EMT/migration readouts, single lab","pmids":["41092691"],"is_preprint":false}],"current_model":"GSDMB is a pore-forming gasdermin family protein whose N-terminal domain, when released by granzyme A (GZMA) cleavage at Lys244 (mediated via a dimerization-dependent exosite mechanism), forms 27-fold-symmetric pores in target cell membranes to execute pyroptosis; this activity is strictly dependent on the presence of exon-6-derived elements (present in isoforms 3/4 but absent in isoforms 1/2), which constitute a belt motif essential for membrane insertion, while isoforms lacking exon 6 act as dominant-negative inhibitors of pyroptosis; additionally, GSDMB exhibits direct bactericidal activity via recognition of phospholipids on Gram-negative bacterial membranes, and is targeted for proteasomal degradation by the Shigella IpaH7.8 ubiquitin ligase that engages the pore-forming domain; beyond cell death, GSDMB promotes non-canonical pyroptosis by binding caspase-4's CARD domain (a function blocked by caspase-7 cleavage at D91), regulates epithelial repair through a PDGF-A/FAK/focal adhesion axis, activates the cGAS-STING pathway by interacting with STING's C-terminus to promote Golgi translocation and IRF3 phosphorylation, induces airway remodeling via 5-LO-dependent TGF-β1 upregulation, and in cancer contexts interacts with STAT3 (stabilized by the deubiquitinase USP24) and IGF2BP1/DUSP6 to modulate proliferation signaling."},"narrative":{"mechanistic_narrative":"GSDMB is a pore-forming gasdermin that executes pyroptosis when its autoinhibited full-length form is cleaved by cytotoxic-lymphocyte granzyme A (GZMA), releasing an N-terminal fragment that assembles into a 27-fold-symmetric membrane pore [PMID:32299851, PMID:36991125]. Cleavage requires GZMA to dimerize and engage an exosite on the autoinhibitory GSDMB C-terminal domain, positioning the protease for productive cut at Lys244 [PMID:41592574]. Pore-forming competence is dictated by alternative splicing of exon 6, which supplies a belt motif essential for membrane insertion: exon-6-containing isoforms 3/4 are pyroptotic, whereas isoforms lacking intact exon 6 are inert and act as dominant-negative blockers of pyroptosis [PMID:36991125, PMID:37115914, PMID:36899106]. GSDMB activity is further gated by proteases that produce inhibitory fragments—caspase-7 cleaves at D91 to generate a C-terminal fragment that rebinds and neutralizes the N-domain, while neutrophil elastase and caspases yield non-cytotoxic products [PMID:36899106, PMID:37591921]. Beyond pore formation, the GSDMB N-domain (residues 1–91) binds the caspase-4 CARD to promote non-canonical pyroptosis through GSDMD cleavage [PMID:30321352, PMID:37591921], and GSDMB exerts direct bactericidal activity by recognizing phospholipids on Gram-negative bacterial membranes; the Shigella effector IpaH7.8 counters this by ubiquitinating the GSDMB pore-forming domain for proteasomal degradation [PMID:36991125, PMID:34022140, PMID:36599845]. Independent of cell death, GSDMB promotes epithelial restitution via a PDGF-A/FAK/focal-adhesion axis [PMID:35021065], activates cGAS-STING signaling by binding the STING C-terminus to drive Golgi translocation and IRF3 phosphorylation [PMID:38737375], and in airway and cancer contexts couples to 5-LO/TGF-β1, STAT3, and IGF2BP1/DUSP6 to modulate remodeling and proliferation [PMID:27799535, PMID:34326684, PMID:39353395].","teleology":[{"year":2020,"claim":"Established the central activating event by showing that cytotoxic-lymphocyte GZMA cleaves GSDMB to unleash pore-forming pyroptosis, placing GSDMB downstream of immune killing rather than as a passive marker.","evidence":"In vitro cleavage, NK/CTL co-culture killing assays, IFN-γ induction, and mouse tumor models","pmids":["32299851"],"confidence":"High","gaps":["Did not resolve the structural basis of cleavage specificity","Isoform dependence of pyroptosis not yet defined"]},{"year":2008,"claim":"Initial localization studies framed GSDMB as a cytoplasmic, sometimes nuclear, protein with secretory-pathway-associated vesicular staining and a proliferative effect, before any pore-forming function was known.","evidence":"Immunohistochemistry, GFP-fusion imaging, and proliferation assays in cancer cell lines","pmids":["18038310","18633457"],"confidence":"Low","gaps":["No functional consequence of localization established","Cell-type discrepancy in nuclear vs cytoplasmic localization unexplained"]},{"year":2010,"claim":"Identified a cis-regulatory mechanism by showing an upstream Alu element with an IKZF binding motif positively drives GSDMB expression, addressing how the gene is transcriptionally controlled.","evidence":"Reporter assays with intact, deleted, and mutated Alu constructs plus patient tissue expression","pmids":["20410667"],"confidence":"Medium","gaps":["IKZF binding inferred from motif, not directly demonstrated","Regulation in non-cancer tissue not addressed"]},{"year":2016,"claim":"Linked GSDMB to airway disease by showing it drives TGF-β1 expression via 5-LO and causes airway hyperresponsiveness in transgenic mice, a death-independent role.","evidence":"Overexpression in bronchial epithelium, 5-LO siRNA epistasis, and a hGSDMB transgenic mouse","pmids":["27799535"],"confidence":"Medium","gaps":["Mechanism linking GSDMB to 5-LO induction unknown","Relationship to pore-forming function not established"]},{"year":2019,"claim":"Revealed a non-pore-forming role in inflammasome signaling by showing the GSDMB N-domain binds the caspase-4 CARD to promote non-canonical pyroptosis and GSDMD cleavage.","evidence":"Co-IP of GSDMB-caspase-4 CARD, caspase activity assays, and GSDMD cleavage readouts","pmids":["30321352"],"confidence":"Medium","gaps":["Single-lab Co-IP without structural validation","How GSDMB enhances caspase-4 activity mechanistically unresolved"]},{"year":2021,"claim":"Defined the host-pathogen conflict and a direct antibacterial function: Shigella IpaH7.8 ubiquitinates GSDMB for proteasomal destruction, while GSDMB itself kills Gram-negative bacteria by recognizing their membrane phospholipids.","evidence":"Reciprocal Co-IP, ubiquitination and proteasome-inhibitor assays, bacterial lipid-binding, and NK killing assays","pmids":["34022140"],"confidence":"High","gaps":["Structural basis of IpaH7.8 recognition not yet determined here","Specificity of bacterial phospholipid recognition incompletely defined"]},{"year":2021,"claim":"Connected GSDMB to oncogenic signaling by identifying a USP24/GSDMB/STAT3 axis that stabilizes GSDMB and promotes bladder cancer growth.","evidence":"Co-IP/MS, STAT3 phosphorylation assays, USP24 inhibitor treatment, and xenografts","pmids":["34326684"],"confidence":"Medium","gaps":["Direct vs indirect GSDMB-STAT3 interaction not resolved","How GSDMB modulates glucose metabolism mechanistically unknown"]},{"year":2022,"claim":"Established a pyroptosis-independent epithelial repair function, showing GSDMB drives wound closure via PDGF-A-mediated FAK phosphorylation and focal-adhesion turnover, with disease SNPs disrupting this.","evidence":"Knockout/knockdown in epithelial cells and organoids, wound-closure, focal-adhesion, and FAK phosphorylation assays","pmids":["35021065"],"confidence":"High","gaps":["Molecular link between GSDMB and PDGF-A signaling undefined","Relation to the pore-forming domain not established"]},{"year":2023,"claim":"Provided the structural mechanism of pore formation and bacterial subversion: the cryo-EM 27-fold pore and IpaH7.8-GSDMB crystal structures, demonstrating that exon-6-derived belt elements are essential for membrane insertion.","evidence":"X-ray crystallography of full-length GSDMB and IpaH7.8 complex, cryo-EM of the pore, plus mutagenesis","pmids":["36991125","36599845"],"confidence":"High","gaps":["Mechanism of pore nucleation kinetics not resolved","Lipid selectivity of human membrane pores incompletely defined"]},{"year":2023,"claim":"Resolved the functional logic of splicing and proteolysis: exon-6 isoforms (3/4) are cytotoxic while exon-6-deficient isoforms act as dominant-negative inhibitors, and elastase/caspase cleavage generates non-cytotoxic fragments that gate death.","evidence":"Isoform expression and GZMA/elastase/caspase cleavage assays, NK killing, dominant-negative experiments, and mitochondrial damage assays","pmids":["37115914","36899106"],"confidence":"High","gaps":["Physiological balance of isoform expression in tissues not quantified","Mechanism of dominant-negative inhibition structurally undefined"]},{"year":2023,"claim":"Identified an apoptosis-coupled brake: caspase-7 cleaves GSDMB at D91, generating a C-terminal fragment that rebinds the N-domain to block non-canonical pyroptosis.","evidence":"Caspase-7 cleavage assays, Co-IP of the auto-inhibitory interaction, bacterial infection and septic mouse models","pmids":["37591921"],"confidence":"Medium","gaps":["Single-lab interaction mapping without structure","Crosstalk timing between apoptosis and pyroptosis unresolved"]},{"year":2024,"claim":"Expanded GSDMB into innate antiviral signaling by showing it binds the STING C-terminus to drive Golgi translocation and IRF3 phosphorylation, and identified pharmacological control of its activation via 4-OI modifying GZMA.","evidence":"Co-IP, STING translocation imaging, IRF3 phosphorylation readouts, and MS-based identification of 4-OI sites on GZMA","pmids":["38737375","38982510"],"confidence":"Medium","gaps":["GSDMB-STING interaction shown in single lung-cell context","Whether STING role depends on pore formation unknown"]},{"year":2024,"claim":"Linked GSDMB to anti-proliferative signaling in colorectal cancer through an IGF2BP1/DUSP6/ERK axis, contrasting with its pro-proliferative role in other cancers.","evidence":"Co-IP of GSDMB-IGF2BP1, IGF2BP1-DUSP6 3'-UTR binding, ERK phosphorylation assays, and transgenic/organoid models","pmids":["39353395"],"confidence":"Medium","gaps":["Tissue-context basis for opposing cancer roles unexplained","Direct vs indirect GSDMB effect on IGF2BP1 activity unclear"]},{"year":2025,"claim":"Added transcriptional control and an EMT phenotype, showing GATA1 binds the GSDMB promoter and GSDMB overexpression promotes EMT, proliferation, and migration in TGF-β1-treated bronchial cells.","evidence":"ChIP for GATA1 binding, gain-of-function with EMT marker, proliferation and migration assays","pmids":["41092691"],"confidence":"Medium","gaps":["Relationship of EMT role to pore-forming activity undefined","Single cell-line context"]},{"year":2026,"claim":"Defined the molecular basis of GZMA selectivity for GSDMB: a dimerization-dependent exosite engages the autoinhibitory GSDMB-C domain in 2:2 stoichiometry to enable cleavage at Lys244, explaining why mouse GZMA fails to activate GSDMB.","evidence":"Crystal structure of the GZMA-GSDMB-C complex, binding affinity and dimerization analysis, and exosite mutagenesis with cleavage assays","pmids":["41592574"],"confidence":"High","gaps":["How exosite engagement is regulated in cells unknown","Whether other granzymes use analogous exosites untested"]},{"year":null,"claim":"It remains unresolved how GSDMB's pyroptotic, antibacterial, epithelial-repair, STING-signaling, and proliferative functions are coordinated within a single cell, and which domains/isoforms partition between these roles.","evidence":"No single study integrates the death-dependent and death-independent activities","pmids":[],"confidence":"Low","gaps":["No unified model linking pore-forming and signaling functions","Tissue-specific isoform expression maps lacking","In vivo relevance of non-pyroptotic axes incompletely established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,1]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,6,7]},{"term_id":"GO:0090729","term_label":"toxin activity","supporting_discovery_ids":[2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,17]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,10,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,1]}],"complexes":[],"partners":["GZMA","IPAH7.8","CASP4","CASP7","STING1","STAT3","USP24","IGF2BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAX9","full_name":"Gasdermin-B","aliases":["Gasdermin-like protein"],"length_aa":416,"mass_kda":47.3,"function":"Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death (PubMed:32299851). This form constitutes the precursor of the pore-forming protein: upon cleavage, the released N-terminal moiety (Gasdermin-B, N-terminal) binds to membranes and forms pores, triggering pyroptosis (PubMed:32299851). Also acts as a regulator of epithelial cell repair independently of programmed cell death: translocates to the plasma membrane and promotes epithelial maintenance and repair by regulating PTK2/FAK-mediated phosphorylation of PDGFA (PubMed:35021065) Pore-forming protein produced by cleavage by granzyme A (GZMA), which causes membrane permeabilization and pyroptosis in target cells of cytotoxic T and natural killer (NK) cells (PubMed:27281216, PubMed:32299851). Key downstream mediator of granzyme-mediated cell death: (1) granzyme A (GZMA), delivered to target cells from cytotoxic T- and NK-cells, (2) specifically cleaves Gasdermin-B to generate this form (PubMed:32299851). After cleavage, moves to the plasma membrane, homooligomerizes within the membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:32299851, PubMed:36599845, PubMed:36991122, PubMed:36991125). The different isoforms recognize and bind different phospholipids on membranes, promoting cell death of different target cells (PubMed:34022140, PubMed:36157507, PubMed:36991122, PubMed:36991125) Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis (PubMed:28154144, PubMed:36157507, PubMed:36899106, PubMed:36991122, PubMed:36991125). Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:28154144, PubMed:36157507, PubMed:36899106, PubMed:36991122, PubMed:36991125). Recognizes and binds membrane inner leaflet lipids of human cells, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, and more weakly to phosphatidic acid (PubMed:28154144, PubMed:36157507). Also binds sufatide, a component of the apical membrane of epithelial cells (PubMed:28154144) Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and mediates pyroptosis of human cells (PubMed:36899106, PubMed:36991122, PubMed:36991125). Following cleavage and activation by granzyme A (GZMA), the N-terminal part binds to membrane inner leaflet lipids, homooligomerizes within the human plasma membrane and forms pores of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis (PubMed:36899106, PubMed:36991122, PubMed:36991125) Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death and specifically mediates cell death of Gram-negative bacteria in response to infection (PubMed:34022140). Following cleavage and activation by granzyme A (GZMA), the N-terminal part recognizes and binds phospholipids found on Gram-negative bacterial membranes, such as lipid A and cariolipin, homooligomerizes within the bacterial membranes and forms pores, triggering pyroptosis followed by cell death (PubMed:34022140). In contrast to isoform 4, does not bind to membrane inner leaflet lipids of host human cell, such as phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate (PubMed:34022140) Not able to trigger pyroptosis Not able to trigger pyroptosis","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TAX9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GSDMB","classification":"Not Classified","n_dependent_lines":42,"n_total_lines":1208,"dependency_fraction":0.0347682119205298},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GSDMB","total_profiled":1310},"omim":[{"mim_id":"611403","title":"ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 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1","ntpm":44.7}],"url":"https://www.proteinatlas.org/search/GSDMB"},"hgnc":{"alias_symbol":["PRO2521"],"prev_symbol":["GSDML"]},"alphafold":{"accession":"Q8TAX9","domains":[{"cath_id":"-","chopping":"5-187_194-228","consensus_level":"high","plddt":66.5718,"start":5,"end":228},{"cath_id":"-","chopping":"250-404","consensus_level":"high","plddt":83.2085,"start":250,"end":404}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAX9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAX9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAX9-F1-predicted_aligned_error_v6.png","plddt_mean":71.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GSDMB","jax_strain_url":"https://www.jax.org/strain/search?query=GSDMB"},"sequence":{"accession":"Q8TAX9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAX9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAX9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAX9"}},"corpus_meta":[{"pmid":"32299851","id":"PMC_32299851","title":"Granzyme 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(GZMA) from cytotoxic lymphocytes directly cleaves GSDMB, unleashing its pore-forming activity and triggering pyroptosis in target cells. NK cells and cytotoxic T lymphocytes kill GSDMB-positive cells through this mechanism. IFN-γ upregulates GSDMB expression and promotes pyroptosis. Introducing GZMA-cleavable GSDMB into mouse cancer cells promotes tumor clearance in vivo.\",\n      \"method\": \"In vitro cleavage assays, cell death assays, NK/CTL co-culture killing assays, mouse tumor models, IFN-γ treatment experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro cleavage, cell killing assays, mutagenesis, in vivo models), replicated by multiple subsequent studies\",\n      \"pmids\": [\"32299851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure of IpaH7.8-GSDMB complex reveals how the Shigella flexneri ubiquitin-ligase effector IpaH7.8 recognizes the GSDMB pore-forming domain and ubiquitinates it for proteasomal degradation. Full-length GSDMB crystal structure shows stronger autoinhibition than other gasdermins. Presence of exon 6 in GSDMB isoforms dictates pore-forming/pyroptotic activity. Cryo-EM structure of the 27-fold-symmetric GSDMB pore reveals conformational changes driving pore formation and an essential role for exon-6-derived elements in pore assembly.\",\n      \"method\": \"X-ray crystallography (IpaH7.8-GSDMB complex and full-length GSDMB), cryo-EM (GSDMB pore), biochemical ubiquitination assays, isoform pyroptosis assays, mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + cryo-EM structure + mutagenesis + functional assays in a single rigorous study\",\n      \"pmids\": [\"36991125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Shigella flexneri effector IpaH7.8 ubiquitinates GSDMB and targets it for 26S proteasome-dependent destruction, protecting Shigella from NK cell bactericidal killing. GSDMB exhibits direct microbiocidal activity through recognition of phospholipids found on Gram-negative bacterial membranes, killing bacteria directly rather than by lysing host cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, NK cell killing assays, bacterial membrane lipid-binding assays, GSDMB knockdown/overexpression\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional killing assays, lipid-binding experiments, genetic knockdown with defined phenotypic readouts; replicated structurally by subsequent papers\",\n      \"pmids\": [\"34022140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GSDMB promotes epithelial restitution and repair independent of pyroptosis in inflamed colonocytes. GSDMB-deficient epithelial cells show hyper-adhesiveness, enhanced formation of vinculin-based focal adhesions, and arrest in wound closure. This is dependent on PDGF-A-mediated FAK phosphorylation. Disease-associated GSDMB SNPs disrupt epithelial restitution/repair.\",\n      \"method\": \"GSDMB knockout/knockdown in epithelial cells and organoids, in vitro wound closure assays, transcriptome profiling, focal adhesion analysis, FAK phosphorylation assays, single-cell analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype, multiple orthogonal assays (wound closure, focal adhesion, phosphorylation, transcriptomics), single lab\",\n      \"pmids\": [\"35021065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GSDMB directly binds the CARD domain of caspase-4, promoting caspase-4 activity, which is required for cleavage of GSDMD in non-canonical pyroptosis. Downregulation of GSDMB alleviates GSDMD cleavage and cell death; overexpression promotes GSDMD cleavage and LDH release.\",\n      \"method\": \"Co-immunoprecipitation (GSDMB-caspase-4 CARD domain binding), caspase activity assays, GSDMB knockdown/overexpression, LDH release assays, Western blot for GSDMD cleavage\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for binding, functional assays for caspase-4 activity and GSDMD cleavage, single lab with multiple methods\",\n      \"pmids\": [\"30321352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GSDMB overexpression in primary human bronchial epithelium increases expression of TGF-β1 and 5-lipoxygenase (5-LO). GSDMB induces TGF-β1 expression via induction of 5-LO, as knockdown of 5-LO in GSDMB-overexpressing cells inhibited TGF-β1 expression. Transgenic mice expressing human GSDMB show spontaneous airway hyperresponsiveness and remodeling without inflammation.\",\n      \"method\": \"Overexpression in primary human bronchial epithelium, siRNA knockdown of 5-LO, transgenic mouse model (hGSDMBZp3-Cre), gene expression assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via siRNA knockdown, in vitro and in vivo models, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"27799535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GSDMB splicing isoforms are functionally distinct: isoforms 3 and 4 (containing exon 6) cause pyroptosis after GZMA cleavage, while isoforms 1, 2, and 5 (lacking intact exon 6) do not. Non-cytotoxic GSDMB N-terminal fragments block pyroptosis caused by cytotoxic isoforms in a dominant-negative manner. Upon NK cell attack, different isoforms lead to distinct cell death modes (pyroptosis, mixed pyroptosis/apoptosis, or apoptosis only).\",\n      \"method\": \"Isoform expression and GZMA cleavage assays, NK cell killing assays, cell death phenotype analysis (pyroptosis vs apoptosis markers), dominant-negative experiments, structural analysis of belt motif\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple isoforms tested with functional assays, NK cell killing experiments, dominant-negative validation, consistent with structural data from other labs\",\n      \"pmids\": [\"37115914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Exon 6 translation is essential for GSDMB-mediated pyroptosis; GSDMB isoforms lacking exon 6 (GSDMB1-2) cannot cause cancer cell death. GSDMB N-terminal constructs containing exon 6 provoke cell membrane lysis and concomitant mitochondrial damage. Specific residues within exon 6 and other N-terminal domain regions are important for GSDMB-triggered cell death and mitochondrial impairment. Neutrophil elastase and caspase cleavage of GSDMB produces short N-terminal fragments with no cytotoxic activity, suggesting these proteases act as inhibitory mechanisms of pyroptosis.\",\n      \"method\": \"Isoform expression and cell death assays, mutagenesis of specific residues, mitochondrial damage assays, protease cleavage assays (GZMA, neutrophil elastase, caspases), cell membrane lysis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution of cleavage by multiple proteases, mutagenesis of functional residues, multiple orthogonal death assays, single lab\",\n      \"pmids\": [\"36899106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure of GSDMB in complex with IpaH7.8 identifies membrane engagement sites of GSDMB. Structural analysis reveals how IpaH7.8 interacts with GSDMB and ubiquitinates it. Two residues in the α1-α2 loop of mouse GSDMD make it invulnerable to IpaH7.8-mediated degradation (non-identical to human).\",\n      \"method\": \"X-ray crystallography (GSDMB-IpaH7.8 complex), biochemical ubiquitination assays, mutagenesis of α1-α2 loop residues, functional degradation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis and biochemical validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36599845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Caspase-7 cleaves GSDMB at the D91 site during apoptosis, generating a C-terminal fragment (92–417 aa) that binds back to the GSDMB N-terminus (1–91 aa) to block GSDMB's pro-pyroptotic function, thereby inhibiting non-canonical pyroptosis. The GSDMB N-domain (1–91 aa) is important for binding caspase-4 and promoting non-canonical pyroptosis. During bacterial infection (E. coli, S. Typhimurium) and in a septic mouse model, inhibition of caspase-7/GSDMB axis increased pyroptotic cell death.\",\n      \"method\": \"Caspase-7 cleavage assays, co-immunoprecipitation (GSDMB-C binding GSDMB-N, GSDMB binding caspase-4), cell death assays with bacterial infection models, caspase-7 inhibitor and knockout mouse experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cleavage site identified with functional consequence, Co-IP of auto-inhibitory interaction, in vivo mouse model, single lab\",\n      \"pmids\": [\"37591921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GSDMB interacts with STAT3 to increase STAT3 phosphorylation and modulate glucose metabolism in bladder cancer cells. USP24 (a deubiquitinase) stabilizes GSDMB by preventing its degradation, activating downstream STAT3 signaling. This USP24/GSDMB/STAT3 axis promotes bladder cancer growth.\",\n      \"method\": \"Mass spectrometry and co-immunoprecipitation (GSDMB-STAT3 and GSDMB-USP24 interactions), GSDMB overexpression/knockdown, STAT3 phosphorylation assays, USP24 inhibitor treatment, xenograft tumor models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus MS for interactions, functional assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"34326684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GSDMB interacts with the C-terminus of STING and promotes translocation of STING to the Golgi, leading to phosphorylation of IRF3 and induction of interferons and interferon-stimulated genes (ISGs) via the cGAS-STING pathway in bronchial epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation (GSDMB-STING interaction), immunofluorescence (STING Golgi translocation), IRF3 phosphorylation assays, GSDMB overexpression and knockout in BEAS-2B and primary bronchial epithelial cells, qPCR/ELISA for IFN/ISG expression\",\n      \"journal\": \"Journal of respiratory biology and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, localization imaging, gain- and loss-of-function with defined signaling readout, single lab\",\n      \"pmids\": [\"38737375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"4-Octyl itaconate (4-OI) inhibits GSDMB-mediated pyroptosis by directly modifying Cys54, Cys148, and Ser212 on granzyme A (GZMA), thereby blocking GZMA-mediated cleavage of GSDMB rather than acting on GSDMB itself.\",\n      \"method\": \"Mass spectrometry-based identification of 4-OI modification sites on GZMA, GZMA cleavage assays, pyroptosis assays, transgenic mouse colitis model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification of covalent modification sites on GZMA with functional cleavage and pyroptosis assays, single lab\",\n      \"pmids\": [\"38982510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GSDMB interacts with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which binds to and recognizes the 3'-UTR of DUSP6 mRNA, enhancing DUSP6 protein translation and inhibiting downstream ERK phosphorylation, thereby suppressing colorectal cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (GSDMB-IGF2BP1), RNA-binding assays (IGF2BP1-DUSP6 3'-UTR), ERK phosphorylation assays, GSDMB transgenic mouse model, organoid experiments\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for protein interaction, mRNA binding assay, downstream signaling assay, in vivo model; single lab\",\n      \"pmids\": [\"39353395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Human GZMA targets GSDMB via specific, high-affinity binding to the autoinhibitory GSDMB-C domain. GZMA dimerization is required for this interaction. A crystal structure of the GZMA-GSDMB-C complex shows 2:2 stoichiometry with an exosite at each of two symmetric dimer interfaces in GZMA; the exosite engages a two-loop-organized site in the GSDMB-C domain, enabling functional cleavage at Lys244. Mouse GZMA has a less efficient exosite; mutation of the mouse GZMA exosite enabled it to efficiently cleave and activate GSDMB.\",\n      \"method\": \"X-ray crystallography (GZMA-GSDMB-C complex), binding affinity measurements, GZMA dimerization analysis, mutagenesis of exosite residues, cleavage assays with mouse/human GZMA variants\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with defined stoichiometry, mutagenesis of functional exosite, biochemical cleavage assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41592574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An Alu element in the 5' regulatory region upstream of GSDMB positively regulates GSDMB expression. A putative IKZF binding motif within this Alu element is crucial for upregulating GSDMB expression, as shown by reporter assays with intact, deleted, and mutated Alu elements.\",\n      \"method\": \"Reporter assays with intact, deleted, and mutated Alu element constructs; expression analysis in gastric cancer patient tissues\",\n      \"journal\": \"Genes & genetic systems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with multiple deletion/mutation constructs identifying functional element, single lab\",\n      \"pmids\": [\"20410667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GSDMB (GSDML) protein is localized to the cytoplasm in most cell types, but shows a distinctive vesicular staining pattern in the apical region of gastric chief cells and colonic surface mucous cells, and the basal region of neuroendocrine cells, suggesting involvement in a secretory pathway.\",\n      \"method\": \"Immunohistochemistry and immunoblotting using anti-peptide antibodies developed against GSDML; in vitro transcription-translation for antibody specificity verification\",\n      \"journal\": \"Pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by IHC without functional consequence established, single lab\",\n      \"pmids\": [\"18038310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GFP-GSDMB (GSDML1) fusion protein localizes predominantly to the nucleus in MCF7 and HeLa cells but exclusively to the cytoplasm in HepG2 cells, indicating cell-type-dependent subcellular localization. Ectopic expression of GSDMB1 enhanced cell growth, while inhibition of its endogenous expression decreased proliferation.\",\n      \"method\": \"GFP fusion protein live cell imaging, siRNA knockdown and overexpression, BrdU incorporation assay, MTT-equivalent proliferation assays\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by GFP fusion, proliferation assays without clear pathway placement, single lab\",\n      \"pmids\": [\"18633457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GATA1 binds to the promoter region of GSDMB and facilitates its expression. GSDMB overexpression upregulates mesenchymal markers and promotes epithelial-mesenchymal transition (EMT), as well as proliferation and migration in TGF-β1-treated bronchial epithelial cells.\",\n      \"method\": \"Chromatin immunoprecipitation (GATA1 binding to GSDMB promoter), GSDMB overexpression in Beas-2B cells with TGF-β1 treatment, EMT marker assays, proliferation and migration assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP for transcription factor binding, gain-of-function with defined EMT/migration readouts, single lab\",\n      \"pmids\": [\"41092691\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GSDMB is a pore-forming gasdermin family protein whose N-terminal domain, when released by granzyme A (GZMA) cleavage at Lys244 (mediated via a dimerization-dependent exosite mechanism), forms 27-fold-symmetric pores in target cell membranes to execute pyroptosis; this activity is strictly dependent on the presence of exon-6-derived elements (present in isoforms 3/4 but absent in isoforms 1/2), which constitute a belt motif essential for membrane insertion, while isoforms lacking exon 6 act as dominant-negative inhibitors of pyroptosis; additionally, GSDMB exhibits direct bactericidal activity via recognition of phospholipids on Gram-negative bacterial membranes, and is targeted for proteasomal degradation by the Shigella IpaH7.8 ubiquitin ligase that engages the pore-forming domain; beyond cell death, GSDMB promotes non-canonical pyroptosis by binding caspase-4's CARD domain (a function blocked by caspase-7 cleavage at D91), regulates epithelial repair through a PDGF-A/FAK/focal adhesion axis, activates the cGAS-STING pathway by interacting with STING's C-terminus to promote Golgi translocation and IRF3 phosphorylation, induces airway remodeling via 5-LO-dependent TGF-β1 upregulation, and in cancer contexts interacts with STAT3 (stabilized by the deubiquitinase USP24) and IGF2BP1/DUSP6 to modulate proliferation signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GSDMB is a pore-forming gasdermin that executes pyroptosis when its autoinhibited full-length form is cleaved by cytotoxic-lymphocyte granzyme A (GZMA), releasing an N-terminal fragment that assembles into a 27-fold-symmetric membrane pore [#0, #1]. Cleavage requires GZMA to dimerize and engage an exosite on the autoinhibitory GSDMB C-terminal domain, positioning the protease for productive cut at Lys244 [#14]. Pore-forming competence is dictated by alternative splicing of exon 6, which supplies a belt motif essential for membrane insertion: exon-6-containing isoforms 3/4 are pyroptotic, whereas isoforms lacking intact exon 6 are inert and act as dominant-negative blockers of pyroptosis [#1, #6, #7]. GSDMB activity is further gated by proteases that produce inhibitory fragments—caspase-7 cleaves at D91 to generate a C-terminal fragment that rebinds and neutralizes the N-domain, while neutrophil elastase and caspases yield non-cytotoxic products [#7, #9]. Beyond pore formation, the GSDMB N-domain (residues 1–91) binds the caspase-4 CARD to promote non-canonical pyroptosis through GSDMD cleavage [#4, #9], and GSDMB exerts direct bactericidal activity by recognizing phospholipids on Gram-negative bacterial membranes; the Shigella effector IpaH7.8 counters this by ubiquitinating the GSDMB pore-forming domain for proteasomal degradation [#1, #2, #8]. Independent of cell death, GSDMB promotes epithelial restitution via a PDGF-A/FAK/focal-adhesion axis [#3], activates cGAS-STING signaling by binding the STING C-terminus to drive Golgi translocation and IRF3 phosphorylation [#11], and in airway and cancer contexts couples to 5-LO/TGF-β1, STAT3, and IGF2BP1/DUSP6 to modulate remodeling and proliferation [#5, #10, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the central activating event by showing that cytotoxic-lymphocyte GZMA cleaves GSDMB to unleash pore-forming pyroptosis, placing GSDMB downstream of immune killing rather than as a passive marker.\",\n      \"evidence\": \"In vitro cleavage, NK/CTL co-culture killing assays, IFN-γ induction, and mouse tumor models\",\n      \"pmids\": [\"32299851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of cleavage specificity\", \"Isoform dependence of pyroptosis not yet defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Initial localization studies framed GSDMB as a cytoplasmic, sometimes nuclear, protein with secretory-pathway-associated vesicular staining and a proliferative effect, before any pore-forming function was known.\",\n      \"evidence\": \"Immunohistochemistry, GFP-fusion imaging, and proliferation assays in cancer cell lines\",\n      \"pmids\": [\"18038310\", \"18633457\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence of localization established\", \"Cell-type discrepancy in nuclear vs cytoplasmic localization unexplained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified a cis-regulatory mechanism by showing an upstream Alu element with an IKZF binding motif positively drives GSDMB expression, addressing how the gene is transcriptionally controlled.\",\n      \"evidence\": \"Reporter assays with intact, deleted, and mutated Alu constructs plus patient tissue expression\",\n      \"pmids\": [\"20410667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IKZF binding inferred from motif, not directly demonstrated\", \"Regulation in non-cancer tissue not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked GSDMB to airway disease by showing it drives TGF-β1 expression via 5-LO and causes airway hyperresponsiveness in transgenic mice, a death-independent role.\",\n      \"evidence\": \"Overexpression in bronchial epithelium, 5-LO siRNA epistasis, and a hGSDMB transgenic mouse\",\n      \"pmids\": [\"27799535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GSDMB to 5-LO induction unknown\", \"Relationship to pore-forming function not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-pore-forming role in inflammasome signaling by showing the GSDMB N-domain binds the caspase-4 CARD to promote non-canonical pyroptosis and GSDMD cleavage.\",\n      \"evidence\": \"Co-IP of GSDMB-caspase-4 CARD, caspase activity assays, and GSDMD cleavage readouts\",\n      \"pmids\": [\"30321352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without structural validation\", \"How GSDMB enhances caspase-4 activity mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the host-pathogen conflict and a direct antibacterial function: Shigella IpaH7.8 ubiquitinates GSDMB for proteasomal destruction, while GSDMB itself kills Gram-negative bacteria by recognizing their membrane phospholipids.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination and proteasome-inhibitor assays, bacterial lipid-binding, and NK killing assays\",\n      \"pmids\": [\"34022140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IpaH7.8 recognition not yet determined here\", \"Specificity of bacterial phospholipid recognition incompletely defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected GSDMB to oncogenic signaling by identifying a USP24/GSDMB/STAT3 axis that stabilizes GSDMB and promotes bladder cancer growth.\",\n      \"evidence\": \"Co-IP/MS, STAT3 phosphorylation assays, USP24 inhibitor treatment, and xenografts\",\n      \"pmids\": [\"34326684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect GSDMB-STAT3 interaction not resolved\", \"How GSDMB modulates glucose metabolism mechanistically unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a pyroptosis-independent epithelial repair function, showing GSDMB drives wound closure via PDGF-A-mediated FAK phosphorylation and focal-adhesion turnover, with disease SNPs disrupting this.\",\n      \"evidence\": \"Knockout/knockdown in epithelial cells and organoids, wound-closure, focal-adhesion, and FAK phosphorylation assays\",\n      \"pmids\": [\"35021065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between GSDMB and PDGF-A signaling undefined\", \"Relation to the pore-forming domain not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the structural mechanism of pore formation and bacterial subversion: the cryo-EM 27-fold pore and IpaH7.8-GSDMB crystal structures, demonstrating that exon-6-derived belt elements are essential for membrane insertion.\",\n      \"evidence\": \"X-ray crystallography of full-length GSDMB and IpaH7.8 complex, cryo-EM of the pore, plus mutagenesis\",\n      \"pmids\": [\"36991125\", \"36599845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of pore nucleation kinetics not resolved\", \"Lipid selectivity of human membrane pores incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the functional logic of splicing and proteolysis: exon-6 isoforms (3/4) are cytotoxic while exon-6-deficient isoforms act as dominant-negative inhibitors, and elastase/caspase cleavage generates non-cytotoxic fragments that gate death.\",\n      \"evidence\": \"Isoform expression and GZMA/elastase/caspase cleavage assays, NK killing, dominant-negative experiments, and mitochondrial damage assays\",\n      \"pmids\": [\"37115914\", \"36899106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance of isoform expression in tissues not quantified\", \"Mechanism of dominant-negative inhibition structurally undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an apoptosis-coupled brake: caspase-7 cleaves GSDMB at D91, generating a C-terminal fragment that rebinds the N-domain to block non-canonical pyroptosis.\",\n      \"evidence\": \"Caspase-7 cleavage assays, Co-IP of the auto-inhibitory interaction, bacterial infection and septic mouse models\",\n      \"pmids\": [\"37591921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction mapping without structure\", \"Crosstalk timing between apoptosis and pyroptosis unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded GSDMB into innate antiviral signaling by showing it binds the STING C-terminus to drive Golgi translocation and IRF3 phosphorylation, and identified pharmacological control of its activation via 4-OI modifying GZMA.\",\n      \"evidence\": \"Co-IP, STING translocation imaging, IRF3 phosphorylation readouts, and MS-based identification of 4-OI sites on GZMA\",\n      \"pmids\": [\"38737375\", \"38982510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GSDMB-STING interaction shown in single lung-cell context\", \"Whether STING role depends on pore formation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked GSDMB to anti-proliferative signaling in colorectal cancer through an IGF2BP1/DUSP6/ERK axis, contrasting with its pro-proliferative role in other cancers.\",\n      \"evidence\": \"Co-IP of GSDMB-IGF2BP1, IGF2BP1-DUSP6 3'-UTR binding, ERK phosphorylation assays, and transgenic/organoid models\",\n      \"pmids\": [\"39353395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-context basis for opposing cancer roles unexplained\", \"Direct vs indirect GSDMB effect on IGF2BP1 activity unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added transcriptional control and an EMT phenotype, showing GATA1 binds the GSDMB promoter and GSDMB overexpression promotes EMT, proliferation, and migration in TGF-β1-treated bronchial cells.\",\n      \"evidence\": \"ChIP for GATA1 binding, gain-of-function with EMT marker, proliferation and migration assays\",\n      \"pmids\": [\"41092691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship of EMT role to pore-forming activity undefined\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the molecular basis of GZMA selectivity for GSDMB: a dimerization-dependent exosite engages the autoinhibitory GSDMB-C domain in 2:2 stoichiometry to enable cleavage at Lys244, explaining why mouse GZMA fails to activate GSDMB.\",\n      \"evidence\": \"Crystal structure of the GZMA-GSDMB-C complex, binding affinity and dimerization analysis, and exosite mutagenesis with cleavage assays\",\n      \"pmids\": [\"41592574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How exosite engagement is regulated in cells unknown\", \"Whether other granzymes use analogous exosites untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how GSDMB's pyroptotic, antibacterial, epithelial-repair, STING-signaling, and proliferative functions are coordinated within a single cell, and which domains/isoforms partition between these roles.\",\n      \"evidence\": \"No single study integrates the death-dependent and death-independent activities\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking pore-forming and signaling functions\", \"Tissue-specific isoform expression maps lacking\", \"In vivo relevance of non-pyroptotic axes incompletely established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 1]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"GO:0090729\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 10, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GZMA\", \"IpaH7.8\", \"CASP4\", \"CASP7\", \"STING1\", \"STAT3\", \"USP24\", \"IGF2BP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}