{"gene":"GBP1","run_date":"2026-04-28T18:06:52","timeline":{"discoveries":[{"year":1999,"finding":"Human GBP1 expression in HeLa cells confers resistance to vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) cytopathic effects and reduces viral progeny production; antisense knockdown of GBP1 in IFN-treated cells partially abrogates the IFN-mediated antiviral effect, demonstrating GBP1 mediates the antiviral response.","method":"Stable transfection (overexpression and antisense knockdown) with viral infection assays measuring cytopathic effect and viral progeny","journal":"Virology","confidence":"High","confidence_rationale":"Tier 2 — clean gain- and loss-of-function with specific viral phenotype readouts, replicated across two viruses","pmids":["10087221"],"is_preprint":false},{"year":2001,"finding":"GBP-1 mediates the anti-proliferative effect of inflammatory cytokines on endothelial cells; this activity is independent of GTPase activity and isoprenylation but specifically requires the C-terminal helical domain of the protein.","method":"Experimental modulation of GBP-1 expression (overexpression/knockdown) in microvascular and macrovascular endothelial cells; domain deletion/mutant analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — gain/loss-of-function with domain-mapping mutagenesis and specific proliferation phenotype, replicated in multiple cell types","pmids":["11598000"],"is_preprint":false},{"year":2013,"finding":"Mouse Gbp1 is recruited to the parasitophorous vacuole (PV) of Toxoplasma gondii in an IFN-γ-dependent manner; virulent T. gondii avoids Gbp1 recruitment via parasite virulence factors ROP18 (serine/threonine kinase) and ROP5 (pseudokinase); increased Gbp1 recruitment correlates with parasite clearance requiring the autophagy protein Atg5; Gbp1-/- mice and macrophages confirm Gbp1 is required for IFN-γ-dependent cell-autonomous control.","method":"Gbp1-/- mice and macrophages; parasite mutants (Δrop18, Δrop5); genetic epistasis with Atg5; IFN-γ activation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic knockouts with clear phenotypic epistasis, both in vitro and in vivo","pmids":["23633952"],"is_preprint":false},{"year":2017,"finding":"Human GBP1 is unique among the seven human GBP paralogs in associating with cytosolic Gram-negative bacteria (Burkholderia thailandensis and Shigella flexneri); GBP1 targets bacteria via a unique C-terminal triple-arginine motif; GBP1-decorated Shigella fail to form actin tails, restricting intracellular motility and cell-to-cell spread; GBP1 also recruits GBP2, GBP3, GBP4, and GBP6 to bacteria; O-antigen of LPS promotes GBP1 targeting.","method":"siRNA knockdown, GBP paralog overexpression, triple-arginine motif mutagenesis, actin tail formation assay, cell-to-cell spread assay, colocalization imaging","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including mutagenesis, functional assays, and imaging with clear phenotypic readout","pmids":["29233899"],"is_preprint":false},{"year":2019,"finding":"Human GBP1 targets Toxoplasma-containing parasitophorous vacuoles through its GTPase activity and prenylation, promoting vacuole disruption and release of Toxoplasma DNA; GBP1 facilitates AIM2 inflammasome detection of Toxoplasma DNA, triggering GSDMD-independent, ASC- and caspase-8-dependent apoptosis in human macrophages; GBP1 also facilitates caspase-4 recruitment to Salmonella, enhancing caspase-4 activation and pyroptosis.","method":"CRISPR/siRNA knockdown, GTPase-dead and prenylation-deficient mutants, inflammasome component knockouts (AIM2, ASC, caspase-8, caspase-4), cell death assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and mutant approaches with specific cell death pathway placement across two pathogens","pmids":["31268602"],"is_preprint":false},{"year":2020,"finding":"Human GBP1 directly binds LPS with high affinity through electrostatic interactions and assembles on the surface of cytosolic Salmonella seconds after vacuole escape, initiating sequential recruitment of GBP2-4 to form a GBP coat; this GBP coat then recruits caspase-4 to the bacterial surface and activates it in the absence of bacteriolysis, constituting a platform for non-canonical inflammasome signaling.","method":"Live-cell imaging, LPS-binding assay, CRISPR knockouts of individual GBPs, caspase-4 recruitment assay, biochemical binding studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — direct LPS-binding biochemistry combined with imaging and genetic knockouts, multiple orthogonal methods","pmids":["32581219"],"is_preprint":false},{"year":2020,"finding":"Human GBP1 directly binds LPS and induces detergent-like LPS clustering through protein polymerization; binding of polymerizing GBP1 to the bacterial surface disrupts the O-antigen barrier, unmasking lipid A, eliciting caspase-4 recruitment, enhancing antibacterial activity of polymyxin B, and blocking the Shigella IcsA outer membrane actin motility factor.","method":"Direct LPS binding assays, protein polymerization assays, bacterial killing assays, caspase-4 recruitment assay, IcsA functional assay, electron microscopy","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of LPS binding and polymerization combined with multiple functional readouts","pmids":["32510692"],"is_preprint":false},{"year":2020,"finding":"GBP1 promotes lysis of Toxoplasma-containing vacuoles and parasite plasma membranes to release Toxoplasma DNA; caspase-1 cleaves and inactivates GBP1 (cleavage at D192), and a cleavage-deficient GBP1-D192E mutant increases caspase-4-driven pyroptosis, revealing a feedback inhibition mechanism.","method":"Cryo-electron microscopy of vacuoles, siRNA knockdown, GBP1 D192E mutagenesis, caspase activity assays, cell death assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of specific caspase cleavage site with functional validation of feedback mechanism","pmids":["32783936"],"is_preprint":false},{"year":2012,"finding":"GBP-1 inhibits intestinal epithelial cell proliferation by suppressing β-catenin/TCF signaling; GBP-1 reduces β-catenin protein levels and β-catenin serine 552 phosphorylation through a non-canonical mechanism independent of GSK-3β or proteasomal degradation.","method":"GBP-1 overexpression and siRNA knockdown; β-catenin/TCF reporter assays; Western blot for β-catenin phosphorylation; GSK-3β and proteasome inhibitor experiments","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal gain/loss-of-function with pathway reporter assays, single lab","pmids":["22692453"],"is_preprint":false},{"year":2016,"finding":"Human GBP1 does not associate with pathogen-containing vacuoles formed by Chlamydia trachomatis, Salmonella typhimurium, or Toxoplasma gondii in human cells; CRISPR deletion of GBP1 results in enhanced early Toxoplasma replication, revealing a role in cell-autonomous immunity independent of vacuole translocation.","method":"CRISPR knockout, ectopic overexpression, live-cell imaging, Toxoplasma replication assays","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with specific proliferation phenotype, single lab, defines spatial restriction","pmids":["26874079"],"is_preprint":false},{"year":2018,"finding":"The α9-helix of GBP-1 is sufficient to inhibit cell proliferation; it binds directly to the DNA-binding domain of the Hippo transcription factor TEAD via the 376VDHLFQK382 sequence; this interaction inhibits TEAD transcriptional activity and downstream target gene expression; mutation of this sequence abrogates both TEAD interaction and anti-proliferative activity, independent of GTPase function.","method":"Protein-binding assays, molecular modeling, site-directed mutagenesis of GBP-1 α9-helix, TEAD reporter assays, siRNA knockdown, cell proliferation assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assay combined with mutagenesis and functional transcriptional readout, mechanistically resolved","pmids":["30120107"],"is_preprint":false},{"year":2021,"finding":"GBP1 forms microcapsules around Shigella flexneri, which blocks septin cage assembly around the bacteria, likely by interfering with the Shigella IcsA outer membrane protein required for both actin-based motility and septin cage formation; S. flexneri that escape GBP1 microcapsules via IpaH9.8-mediated GBP degradation are captured within septin cages, revealing two complementary anti-motility defense pathways.","method":"Live-cell imaging, IpaH9.8 effector assays, GBP1 and septin colocalization assays, actin tail formation assay","journal":"Pathogens and disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — imaging-based mechanistic link between two defense systems, moderate evidence","pmids":["33885766"],"is_preprint":false},{"year":2021,"finding":"GBP1 promotes rupture of Legionella-containing vacuoles (LCVs) in a T4SS-dependent manner, leading to increased cytosolic exposure of bacteria and subsequent inflammasome activation in human macrophages; GBP1 is required for IFN-γ-driven inflammasome responses to Legionella.","method":"CRISPR/siRNA knockdown, LCV integrity assay, inflammasome activation assays, colocalization imaging","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with specific membrane damage phenotype, single lab","pmids":["37737612"],"is_preprint":false},{"year":2021,"finding":"GBP1 antiviral activity against Hepatitis E virus (HEV) is independent of GTPase activity but depends on its capacity to form homodimers; dimerization-competent GBP1 targets the viral capsid protein to the lysosomal compartment for inactivation; GBP1 is required for the antiviral effect of IFN-γ on HEV.","method":"GBP1 overexpression, siRNA knockdown, GTPase-dead and dimerization-deficient mutants, lysosomal targeting assay, viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis of specific domain combined with pathway readout, single lab","pmids":["33472929"],"is_preprint":false},{"year":2023,"finding":"GBP2, like GBP1, can directly bind and aggregate free LPS through protein polymerization; supplementation of either recombinant polymerized GBP1 or GBP2 in an in vitro reaction is sufficient to enhance LPS-induced caspase-4 activation; a GBP1 triple-arginine mutant lacking bacterial binding still rescues pyroptosis in GBP1-KO cells, showing that GBP coat assembly on bacteria is dispensable for pyroptosis—instead, LPS aggregation in the cytosol is sufficient.","method":"In vitro caspase-4 activation assay with recombinant proteins, GBP1/2 overexpression in GBP1-KO cells, triple-arginine motif mutant, LPS binding assays, pyroptosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of caspase-4 activation with recombinant proteins, supported by cell-based mutagenesis","pmids":["37023136"],"is_preprint":false},{"year":2023,"finding":"Shigella effector IpaH9.8 limits GBP1-dependent LPS release from intracytosolic bacteria to suppress caspase-4 activation; in the absence of IpaH9.8, increased LPS is shed from bacteria in a GBP1-dependent manner, promoting caspase-4 activation and pyroptosis.","method":"Shigella effector mutants, GBP1 CRISPR knockout, LPS quantification, caspase-4 activity and pyroptosis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with bacterial effector mutants and host CRISPR KO, mechanistic pathway defined","pmids":["37014865"],"is_preprint":false},{"year":2023,"finding":"PIM1 kinase phosphorylates GBP1, leading to its sequestration by 14-3-3σ, which prevents GBP1 membrane association; IFN-γ induces PIM1 expression, protecting macrophages from GBP1-mediated self-damage; during Toxoplasma infection, the parasite virulence protein TgIST depletes PIM1, increasing GBP1 activity for antimicrobial defense.","method":"Co-immunoprecipitation, phosphorylation assays, PIM1 overexpression/knockdown, 14-3-3σ pulldown, TgIST-expressing parasites, macrophage viability assays, membrane fractionation","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical demonstration of phosphorylation and sequestration, mechanistically linked to cellular protection, multiple orthogonal approaches","pmids":["37797010"],"is_preprint":false},{"year":2024,"finding":"Native cryo-electron tomography of human cells resolved the structure of a massive GBP1 defense complex polymerizing ~30,000 GBP molecules over the surface of gram-negative bacteria; construction requires GTP hydrolysis; GBP1 adopts an extended 'open conformer' for bacterial membrane insertion, establishing a platform that recruits caspase-4 and Gasdermin D; the assembled complex triggers LPS release that activates coassembled caspase-4.","method":"Cryo-electron tomography of infected human cells, GBP1 mutant analysis, quantitative imaging of complex assembly kinetics","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — native structural determination by cryo-ET combined with functional validation, foundational mechanism study","pmids":["38422126"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of soluble and membrane-bound GBP1 oligomers reveal that GBP1 assembles in an outstretched dimeric conformation; a surface-exposed helix in the large GTPase domain contributes to the oligomerization interface; nucleotide-dependent conformational changes coordinate dimerization, oligomerization, and membrane binding to allow pathogen encapsulation.","method":"Cryo-electron microscopy of soluble and membrane-bound GBP1 oligomers, mutagenesis of oligomerization interface helix, nucleotide-binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structures with mutagenesis validation of oligomerization mechanism","pmids":["38267655"],"is_preprint":false},{"year":2023,"finding":"Human GBP1 is recruited to damaged phagosomes/endolysosomes in a GTP-binding and isoprenylation-dependent manner; in vitro lipid-binding assays demonstrate direct binding of GBP1 to PI4P and PI(3,4)P2; live-cell imaging shows GBP1 mediates endolysosomal repair after membrane damage caused by intracellular mycobacteria.","method":"In vitro lipid-binding assay, live-cell imaging, GTP-binding and isoprenylation-deficient mutants, endolysosomal integrity assays, siRNA knockdown","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct lipid binding in vitro combined with cell-based imaging, single lab","pmids":["37298652"],"is_preprint":false},{"year":2014,"finding":"GBP1 incorporates into microtubules via class III β-tubulin and binds the pro-survival kinase PIM1; inhibition of the GBP1:PIM1 interaction by NSC756093 was confirmed by surface plasmon resonance; mutagenesis and modeling identified the binding site at the interface of the helical and LG domains of GBP1.","method":"Surface plasmon resonance, molecular modeling, site-directed mutagenesis, NCI-60 cell panel screening","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct binding assay (SPR) with mutagenesis, functional link to drug resistance, single lab","pmids":["25211704"],"is_preprint":false},{"year":2020,"finding":"GBP1 interacts with phosphoglycerate kinase 1 (PGK1) as confirmed by co-immunoprecipitation and mass spectrometry; GBP1 regulates epithelial-mesenchymal transition (EMT) through PGK1, promoting erlotinib resistance in non-small cell lung cancer cells.","method":"Co-immunoprecipitation, mass spectrometry, GBP1 overexpression/knockdown, rescue experiment with PGK1","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP confirmed interaction with functional rescue, single lab","pmids":["32582960"],"is_preprint":false},{"year":2024,"finding":"GBP1 promotes mitochondrial fission in glioblastoma cells by facilitating movement of Drp1 from the cytosol to the mitochondria; GBP1 co-localizes with Drp1 specifically at mitochondria; elevated GBP1 produces shorter and wider mitochondria consistent with fission; GBP1-mediated fission contributes to cell migration.","method":"Subcellular fractionation, co-localization imaging, Drp1 inhibitor (Mdivi-1) experiments, mitochondrial morphology analysis, migration assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — fractionation and imaging with functional migration readout, single lab","pmids":["39457021"],"is_preprint":false},{"year":2025,"finding":"GBP1 is recruited to actin-rich pedestals induced by extracellular EPEC/EHEC bacteria in a manner independent of direct LPS contact; GBP1 recruitment is driven by pathogen-induced actin remodeling (demonstrated by FcγR-Tir chimeric receptor with sterile actin pedestals); GBP1-dependent caspase-4 trafficking to pedestals leads to pyroptosis and IL-18 release.","method":"Live-cell imaging, chimeric receptor engineering (FcγR-Tir), IgG-coated bead actin pedestal assay, caspase-4 recruitment and pyroptosis assays, in vivo mouse colonocyte imaging","journal":"bioRxiv / mBio (PMID:41040234)","confidence":"Medium","confidence_rationale":"Tier 2 — novel chimeric receptor reconstitution experiment establishing LPS-independent GBP1 recruitment mechanism, peer-reviewed version also exists","pmids":["41040234"],"is_preprint":false}],"current_model":"Human GBP1 is an IFN-γ-inducible large GTPase that, upon GTP hydrolysis, assembles into higher-order polymers and forms a microcapsule/coatomer on cytosolic gram-negative bacteria by directly binding LPS (including lipid A) through electrostatic interactions; this GBP1 coat nucleates recruitment of GBP2–4, caspase-4, and Gasdermin D to create an innate immune signaling platform that triggers caspase-4 activation, LPS release, and pyroptosis (non-canonical inflammasome), while simultaneously disrupting bacterial actin-based motility; GBP1 is also recruited to damaged pathogen-containing vacuoles (promoting rupture and release of microbial ligands for inflammasome detection) and to lipid PI4P-containing damaged endolysosomes (mediating repair); its membrane association and activity are restrained by PIM1 kinase-mediated phosphorylation and subsequent sequestration by 14-3-3σ; in non-immune contexts, GBP1 inhibits cell proliferation via its C-terminal helical domain (α9-helix) by directly binding the TEAD transcription factor and suppressing Hippo pathway target genes, independent of GTPase activity."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that GBP1 is not merely an IFN-induced bystander but an active antiviral effector: overexpression conferred resistance to VSV and EMCV, and antisense knockdown partially abrogated IFN-mediated protection, proving GBP1 contributes directly to the interferon antiviral state.","evidence":"Stable transfection (overexpression and antisense knockdown) of HeLa cells with viral infection assays","pmids":["10087221"],"confidence":"High","gaps":["Antiviral mechanism not identified at the molecular level","No demonstration against intracellular bacteria"]},{"year":2001,"claim":"Revealing a second, non-immune function: GBP1 mediates the anti-proliferative effect of inflammatory cytokines on endothelial cells through its C-terminal helical domain, independent of GTPase activity and isoprenylation, separating its proliferation-suppressive and immune effector functions.","evidence":"Overexpression/knockdown in endothelial cells with domain deletion and GTPase-dead mutant analysis","pmids":["11598000"],"confidence":"High","gaps":["Direct molecular target of the C-terminal domain unknown at this point","Mechanism of proliferation inhibition unresolved"]},{"year":2012,"claim":"Defining a signaling pathway for GBP1's anti-proliferative activity: GBP1 suppresses β-catenin/TCF signaling through a non-canonical mechanism independent of GSK-3β or proteasomal degradation, providing the first pathway-level explanation for proliferation inhibition.","evidence":"GBP1 overexpression/knockdown in intestinal epithelial cells with β-catenin/TCF reporter and phosphorylation assays","pmids":["22692453"],"confidence":"Medium","gaps":["Direct binding to β-catenin not demonstrated","Relationship to C-terminal helical domain not tested","Single laboratory study"]},{"year":2013,"claim":"Demonstrating that GBP1 functions in cell-autonomous anti-parasitic defense: mouse Gbp1 is recruited to Toxoplasma parasitophorous vacuoles in an IFN-γ-dependent manner, and Gbp1-knockout mice show impaired parasite control, establishing GBP1 as essential for anti-Toxoplasma immunity.","evidence":"Gbp1−/− mice and macrophages, parasite virulence factor mutants, genetic epistasis with Atg5","pmids":["23633952"],"confidence":"High","gaps":["Mechanism of vacuolar targeting and disruption unknown","Mouse Gbp1 may not fully recapitulate human GBP1 biology"]},{"year":2017,"claim":"Identifying GBP1 as unique among human GBPs in directly coating cytosolic Gram-negative bacteria: a C-terminal triple-arginine motif mediates bacterial targeting, GBP1 recruits other GBP paralogs, and bacterial coating blocks actin-based motility by interfering with IcsA, revealing GBP1 as the initiator of a multi-GBP antimicrobial platform.","evidence":"siRNA knockdown, paralog overexpression, triple-arginine mutagenesis, actin tail and cell-to-cell spread assays in Shigella/Burkholderia infection","pmids":["29233899"],"confidence":"High","gaps":["Direct LPS binding not yet demonstrated biochemically","Downstream signaling consequences of the coat not defined"]},{"year":2018,"claim":"Resolving the direct molecular target of GBP1's anti-proliferative C-terminal domain: the α9-helix binds the DNA-binding domain of TEAD via a specific seven-residue motif (376VDHLFQK382), suppressing Hippo pathway transcriptional output independent of GTPase activity, unifying the 2001 domain-mapping with a defined target.","evidence":"Protein-binding assays, site-directed mutagenesis of GBP1 α9-helix, TEAD reporter assays, cell proliferation assays","pmids":["30120107"],"confidence":"High","gaps":["Structural basis of GBP1–TEAD interaction not resolved at atomic level","In vivo relevance of TEAD inhibition in tissues not tested"]},{"year":2019,"claim":"Placing GBP1 upstream of inflammasome activation across two pathogens: GBP1 promotes Toxoplasma vacuole disruption and AIM2-dependent detection of parasite DNA while facilitating caspase-4 recruitment to Salmonella, establishing GBP1 as a general gateway for pathogen ligand exposure to cytosolic sensors.","evidence":"CRISPR/siRNA knockdown, GTPase-dead and prenylation-deficient mutants, inflammasome component knockouts in human macrophages","pmids":["31268602"],"confidence":"High","gaps":["How GBP1 physically disrupts vacuolar membranes not defined","Whether GBP1 directly activates or merely presents ligands to caspase-4 unclear"]},{"year":2020,"claim":"Establishing the biochemical basis of the GBP1 antimicrobial coat: GBP1 directly binds LPS with high affinity through electrostatic interactions, polymerizes on bacterial surfaces to disrupt the O-antigen barrier and unmask lipid A, and nucleates sequential GBP2–4 and caspase-4 recruitment, defining the non-canonical inflammasome signaling platform at the bacterial surface.","evidence":"In vitro LPS-binding assays, protein polymerization assays, CRISPR knockouts of individual GBPs, live-cell imaging, electron microscopy","pmids":["32581219","32510692"],"confidence":"High","gaps":["Structural basis of LPS recognition unresolved","Stoichiometry of the GBP1–caspase-4 complex unknown"]},{"year":2020,"claim":"Revealing a feedback control circuit: caspase-1 cleaves GBP1 at D192, inactivating it; a cleavage-resistant D192E mutant enhances caspase-4-driven pyroptosis, showing that inflammasome activation self-limits GBP1 coat function to prevent excessive host cell death.","evidence":"GBP1-D192E mutagenesis, caspase activity assays, cryo-EM of vacuoles, cell death assays","pmids":["32783936"],"confidence":"High","gaps":["Whether other caspases also cleave GBP1 not tested","Physiological significance of this feedback in vivo not established"]},{"year":2021,"claim":"Extending GBP1 antimicrobial function to Legionella: GBP1 promotes rupture of Legionella-containing vacuoles in a T4SS-dependent manner, broadening GBP1's vacuole-disruption role beyond Toxoplasma to multiple intravacuolar pathogens.","evidence":"CRISPR/siRNA knockdown, LCV integrity assays, inflammasome activation in human macrophages","pmids":["37737612"],"confidence":"Medium","gaps":["Molecular mechanism of GBP1-mediated vacuole disruption still unknown","Single laboratory finding"]},{"year":2023,"claim":"Defining the regulatory mechanism that prevents GBP1 self-damage: PIM1 kinase phosphorylates GBP1, causing 14-3-3σ sequestration and preventing membrane association; IFN-γ induces PIM1 for host protection, while Toxoplasma virulence factor TgIST depletes PIM1 to unleash GBP1, establishing phosphorylation as the master switch controlling GBP1 activity.","evidence":"Co-immunoprecipitation, phosphorylation assays, PIM1 overexpression/knockdown, 14-3-3σ pulldown, TgIST parasite experiments, membrane fractionation","pmids":["37797010"],"confidence":"High","gaps":["Specific phosphorylation site(s) on GBP1 not fully mapped","Whether other kinases also regulate GBP1 membrane association unknown"]},{"year":2023,"claim":"Demonstrating that GBP1-mediated LPS aggregation in the cytosol, rather than bacterial coat assembly per se, is sufficient for caspase-4 activation: a triple-arginine mutant unable to target bacteria still rescues pyroptosis, redefining the minimal requirement for non-canonical inflammasome triggering.","evidence":"In vitro caspase-4 activation with recombinant GBP1, triple-arginine mutant in GBP1-KO cells, pyroptosis assays","pmids":["37023136"],"confidence":"High","gaps":["How LPS is released from bacteria into the cytosol for GBP1 aggregation not fully resolved","Relative contribution of coat-dependent vs coat-independent mechanisms in physiological infection unknown"]},{"year":2024,"claim":"Resolving the structural architecture of the GBP1 defense complex at native resolution: cryo-electron tomography and cryo-EM revealed that ~30,000 GBP1 molecules assemble in an extended open-conformer dimeric state on bacterial membranes via GTP hydrolysis-dependent oligomerization, with a surface-exposed helix mediating the oligomerization interface, providing the structural blueprint for the antimicrobial coatomer.","evidence":"Native cryo-electron tomography of infected human cells, cryo-EM of soluble and membrane-bound oligomers, mutagenesis of oligomerization interface","pmids":["38422126","38267655"],"confidence":"High","gaps":["Atomic-resolution structure of GBP1 bound to LPS not available","How conformational changes couple GTP hydrolysis to membrane insertion at the single-molecule level not resolved"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of GBP1 in complex with LPS and caspase-4, the precise phosphorylation sites mediating PIM1/14-3-3σ regulation, whether GBP1's anti-proliferative (TEAD-binding) and antimicrobial (LPS-binding) functions are coordinated or independent in tissues, and the in vivo relevance of GBP1 in human infection and tumor suppression.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution GBP1–LPS co-structure","No in vivo human genetic studies linking GBP1 loss to immunodeficiency","Relationship between anti-proliferative and antimicrobial functions in physiological contexts untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[4,17,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,6,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,5,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6,17,19]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,12,19]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,4,5,6,7,14,15,17]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,5,7,14,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,10,16]}],"complexes":["GBP1 antimicrobial coatomer (GBP1/2/3/4)","Non-canonical inflammasome platform (GBP1/caspase-4/GSDMD)"],"partners":["GBP2","GBP3","GBP4","CASP4","GSDMD","TEAD1","PIM1","YWHAS"],"other_free_text":[]},"mechanistic_narrative":"GBP1 is an interferon-γ-inducible large GTPase that functions as a central effector of cell-autonomous innate immunity against intracellular pathogens while also regulating cell proliferation through a GTPase-independent mechanism. Upon GTP hydrolysis, GBP1 polymerizes into massive coatomer assemblies (~30,000 molecules) on the surface of cytosolic Gram-negative bacteria by directly binding LPS through electrostatic interactions, disrupting the O-antigen barrier to unmask lipid A, and nucleating sequential recruitment of GBP2–4, caspase-4, and Gasdermin D to activate non-canonical inflammasome signaling and pyroptosis [PMID:32510692, PMID:32581219, PMID:38422126]. GBP1 also promotes rupture of pathogen-containing vacuoles to expose microbial ligands (DNA, LPS) for inflammasome detection, with its membrane association restrained by PIM1 kinase-mediated phosphorylation and 14-3-3σ sequestration [PMID:31268602, PMID:37797010]. Independent of its GTPase activity, GBP1 inhibits cell proliferation through its C-terminal α9-helix, which directly binds the TEAD transcription factor to suppress Hippo pathway target gene expression [PMID:30120107]."},"prefetch_data":{"uniprot":{"accession":"P32455","full_name":"Guanylate-binding protein 1","aliases":["GTP-binding protein 1","GBP-1","HuGBP-1","hGBP1","Guanine nucleotide-binding protein 1","Interferon-induced guanylate-binding protein 1"],"length_aa":592,"mass_kda":67.9,"function":"Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (PubMed:16511497, PubMed:22106366, PubMed:29144452, PubMed:31268602, PubMed:32510692, PubMed:32581219, PubMed:37797010, PubMed:7512561). Hydrolyzes GTP to GMP in two consecutive cleavage reactions: GTP is first hydrolyzed to GDP and then to GMP in a processive manner (PubMed:16511497, PubMed:32510692, PubMed:7512561, PubMed:39394410). Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and promotes both inflammasome assembly and autophagy (PubMed:29144452, PubMed:31268602). Acts as a positive regulator of inflammasome assembly by facilitating the detection of inflammasome ligands from pathogens (PubMed:31268602, PubMed:32510692, PubMed:32581219). Involved in the lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol (By similarity). Following pathogen release in the cytosol, forms a protein coat in a GTPase-dependent manner that encapsulates pathogens and promotes the detection of ligands by pattern recognition receptors (PubMed:32510692, PubMed:32581219). Plays a key role in inflammasome assembly in response to infection by Gram-negative bacteria: following pathogen release in the cytosol, forms a protein coat that encapsulates Gram-negative bacteria and directly binds to lipopolysaccharide (LPS), disrupting the O-antigen barrier and unmasking lipid A that is that detected by the non-canonical inflammasome effector CASP4/CASP11 (PubMed:32510692, PubMed:32581219). Also promotes recruitment of proteins that mediate bacterial cytolysis, leading to release double-stranded DNA (dsDNA) that activates the AIM2 inflammasome (PubMed:31268602). Involved in autophagy by regulating bacteriolytic peptide generation via its interaction with ubiquitin-binding protein SQSTM1, which delivers monoubiquitinated proteins to autolysosomes for the generation of bacteriolytic peptides (By similarity). Confers protection to several pathogens, including the bacterial pathogens L.monocytogenes and M.bovis BCG as well as the protozoan pathogen T.gondii (PubMed:31268602). 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LINC01783 Promotes the Progression of Cervical Cancer by Sponging miR-199b-5p to Mediate GBP1 Expression [Retraction].","date":"2022","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/35283646","citation_count":0,"is_preprint":false},{"pmid":"41376480","id":"PMC_41376480","title":"GBP1 as a machine learning-prioritized biomarker and therapeutic target for epstein-barr virus-induced clear cell renal cell carcinoma: multi-omics causal validation.","date":"2025","source":"International journal of surgery (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41376480","citation_count":0,"is_preprint":false},{"pmid":"42012181","id":"PMC_42012181","title":"Swine GBP1 restricts PDCoV replication via disrupting the replication and transcription complex formation.","date":"2026","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/42012181","citation_count":0,"is_preprint":false},{"pmid":"41040234","id":"PMC_41040234","title":"GBP1 recruitment 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thailandensis</i>","date":"2025-03-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.645074","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.17.664572","title":"A 3-genes interferon signature predicts sustained complete remission in pediatric AML patients","date":"2025-07-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.17.664572","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43329,"output_tokens":6298,"usd":0.112228},"stage2":{"model":"claude-opus-4-6","input_tokens":9971,"output_tokens":3807,"usd":0.217545},"total_usd":0.329773,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Human GBP1 expression in HeLa cells confers resistance to vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) cytopathic effects and reduces viral progeny production; antisense knockdown of GBP1 in IFN-treated cells partially abrogates the IFN-mediated antiviral effect, demonstrating GBP1 mediates the antiviral response.\",\n      \"method\": \"Stable transfection (overexpression and antisense knockdown) with viral infection assays measuring cytopathic effect and viral progeny\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain- and loss-of-function with specific viral phenotype readouts, replicated across two viruses\",\n      \"pmids\": [\"10087221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"GBP-1 mediates the anti-proliferative effect of inflammatory cytokines on endothelial cells; this activity is independent of GTPase activity and isoprenylation but specifically requires the C-terminal helical domain of the protein.\",\n      \"method\": \"Experimental modulation of GBP-1 expression (overexpression/knockdown) in microvascular and macrovascular endothelial cells; domain deletion/mutant analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss-of-function with domain-mapping mutagenesis and specific proliferation phenotype, replicated in multiple cell types\",\n      \"pmids\": [\"11598000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mouse Gbp1 is recruited to the parasitophorous vacuole (PV) of Toxoplasma gondii in an IFN-γ-dependent manner; virulent T. gondii avoids Gbp1 recruitment via parasite virulence factors ROP18 (serine/threonine kinase) and ROP5 (pseudokinase); increased Gbp1 recruitment correlates with parasite clearance requiring the autophagy protein Atg5; Gbp1-/- mice and macrophages confirm Gbp1 is required for IFN-γ-dependent cell-autonomous control.\",\n      \"method\": \"Gbp1-/- mice and macrophages; parasite mutants (Δrop18, Δrop5); genetic epistasis with Atg5; IFN-γ activation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic knockouts with clear phenotypic epistasis, both in vitro and in vivo\",\n      \"pmids\": [\"23633952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human GBP1 is unique among the seven human GBP paralogs in associating with cytosolic Gram-negative bacteria (Burkholderia thailandensis and Shigella flexneri); GBP1 targets bacteria via a unique C-terminal triple-arginine motif; GBP1-decorated Shigella fail to form actin tails, restricting intracellular motility and cell-to-cell spread; GBP1 also recruits GBP2, GBP3, GBP4, and GBP6 to bacteria; O-antigen of LPS promotes GBP1 targeting.\",\n      \"method\": \"siRNA knockdown, GBP paralog overexpression, triple-arginine motif mutagenesis, actin tail formation assay, cell-to-cell spread assay, colocalization imaging\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including mutagenesis, functional assays, and imaging with clear phenotypic readout\",\n      \"pmids\": [\"29233899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human GBP1 targets Toxoplasma-containing parasitophorous vacuoles through its GTPase activity and prenylation, promoting vacuole disruption and release of Toxoplasma DNA; GBP1 facilitates AIM2 inflammasome detection of Toxoplasma DNA, triggering GSDMD-independent, ASC- and caspase-8-dependent apoptosis in human macrophages; GBP1 also facilitates caspase-4 recruitment to Salmonella, enhancing caspase-4 activation and pyroptosis.\",\n      \"method\": \"CRISPR/siRNA knockdown, GTPase-dead and prenylation-deficient mutants, inflammasome component knockouts (AIM2, ASC, caspase-8, caspase-4), cell death assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and mutant approaches with specific cell death pathway placement across two pathogens\",\n      \"pmids\": [\"31268602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human GBP1 directly binds LPS with high affinity through electrostatic interactions and assembles on the surface of cytosolic Salmonella seconds after vacuole escape, initiating sequential recruitment of GBP2-4 to form a GBP coat; this GBP coat then recruits caspase-4 to the bacterial surface and activates it in the absence of bacteriolysis, constituting a platform for non-canonical inflammasome signaling.\",\n      \"method\": \"Live-cell imaging, LPS-binding assay, CRISPR knockouts of individual GBPs, caspase-4 recruitment assay, biochemical binding studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct LPS-binding biochemistry combined with imaging and genetic knockouts, multiple orthogonal methods\",\n      \"pmids\": [\"32581219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human GBP1 directly binds LPS and induces detergent-like LPS clustering through protein polymerization; binding of polymerizing GBP1 to the bacterial surface disrupts the O-antigen barrier, unmasking lipid A, eliciting caspase-4 recruitment, enhancing antibacterial activity of polymyxin B, and blocking the Shigella IcsA outer membrane actin motility factor.\",\n      \"method\": \"Direct LPS binding assays, protein polymerization assays, bacterial killing assays, caspase-4 recruitment assay, IcsA functional assay, electron microscopy\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of LPS binding and polymerization combined with multiple functional readouts\",\n      \"pmids\": [\"32510692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GBP1 promotes lysis of Toxoplasma-containing vacuoles and parasite plasma membranes to release Toxoplasma DNA; caspase-1 cleaves and inactivates GBP1 (cleavage at D192), and a cleavage-deficient GBP1-D192E mutant increases caspase-4-driven pyroptosis, revealing a feedback inhibition mechanism.\",\n      \"method\": \"Cryo-electron microscopy of vacuoles, siRNA knockdown, GBP1 D192E mutagenesis, caspase activity assays, cell death assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of specific caspase cleavage site with functional validation of feedback mechanism\",\n      \"pmids\": [\"32783936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GBP-1 inhibits intestinal epithelial cell proliferation by suppressing β-catenin/TCF signaling; GBP-1 reduces β-catenin protein levels and β-catenin serine 552 phosphorylation through a non-canonical mechanism independent of GSK-3β or proteasomal degradation.\",\n      \"method\": \"GBP-1 overexpression and siRNA knockdown; β-catenin/TCF reporter assays; Western blot for β-catenin phosphorylation; GSK-3β and proteasome inhibitor experiments\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain/loss-of-function with pathway reporter assays, single lab\",\n      \"pmids\": [\"22692453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human GBP1 does not associate with pathogen-containing vacuoles formed by Chlamydia trachomatis, Salmonella typhimurium, or Toxoplasma gondii in human cells; CRISPR deletion of GBP1 results in enhanced early Toxoplasma replication, revealing a role in cell-autonomous immunity independent of vacuole translocation.\",\n      \"method\": \"CRISPR knockout, ectopic overexpression, live-cell imaging, Toxoplasma replication assays\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with specific proliferation phenotype, single lab, defines spatial restriction\",\n      \"pmids\": [\"26874079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The α9-helix of GBP-1 is sufficient to inhibit cell proliferation; it binds directly to the DNA-binding domain of the Hippo transcription factor TEAD via the 376VDHLFQK382 sequence; this interaction inhibits TEAD transcriptional activity and downstream target gene expression; mutation of this sequence abrogates both TEAD interaction and anti-proliferative activity, independent of GTPase function.\",\n      \"method\": \"Protein-binding assays, molecular modeling, site-directed mutagenesis of GBP-1 α9-helix, TEAD reporter assays, siRNA knockdown, cell proliferation assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assay combined with mutagenesis and functional transcriptional readout, mechanistically resolved\",\n      \"pmids\": [\"30120107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP1 forms microcapsules around Shigella flexneri, which blocks septin cage assembly around the bacteria, likely by interfering with the Shigella IcsA outer membrane protein required for both actin-based motility and septin cage formation; S. flexneri that escape GBP1 microcapsules via IpaH9.8-mediated GBP degradation are captured within septin cages, revealing two complementary anti-motility defense pathways.\",\n      \"method\": \"Live-cell imaging, IpaH9.8 effector assays, GBP1 and septin colocalization assays, actin tail formation assay\",\n      \"journal\": \"Pathogens and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — imaging-based mechanistic link between two defense systems, moderate evidence\",\n      \"pmids\": [\"33885766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP1 promotes rupture of Legionella-containing vacuoles (LCVs) in a T4SS-dependent manner, leading to increased cytosolic exposure of bacteria and subsequent inflammasome activation in human macrophages; GBP1 is required for IFN-γ-driven inflammasome responses to Legionella.\",\n      \"method\": \"CRISPR/siRNA knockdown, LCV integrity assay, inflammasome activation assays, colocalization imaging\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with specific membrane damage phenotype, single lab\",\n      \"pmids\": [\"37737612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP1 antiviral activity against Hepatitis E virus (HEV) is independent of GTPase activity but depends on its capacity to form homodimers; dimerization-competent GBP1 targets the viral capsid protein to the lysosomal compartment for inactivation; GBP1 is required for the antiviral effect of IFN-γ on HEV.\",\n      \"method\": \"GBP1 overexpression, siRNA knockdown, GTPase-dead and dimerization-deficient mutants, lysosomal targeting assay, viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis of specific domain combined with pathway readout, single lab\",\n      \"pmids\": [\"33472929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GBP2, like GBP1, can directly bind and aggregate free LPS through protein polymerization; supplementation of either recombinant polymerized GBP1 or GBP2 in an in vitro reaction is sufficient to enhance LPS-induced caspase-4 activation; a GBP1 triple-arginine mutant lacking bacterial binding still rescues pyroptosis in GBP1-KO cells, showing that GBP coat assembly on bacteria is dispensable for pyroptosis—instead, LPS aggregation in the cytosol is sufficient.\",\n      \"method\": \"In vitro caspase-4 activation assay with recombinant proteins, GBP1/2 overexpression in GBP1-KO cells, triple-arginine motif mutant, LPS binding assays, pyroptosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of caspase-4 activation with recombinant proteins, supported by cell-based mutagenesis\",\n      \"pmids\": [\"37023136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Shigella effector IpaH9.8 limits GBP1-dependent LPS release from intracytosolic bacteria to suppress caspase-4 activation; in the absence of IpaH9.8, increased LPS is shed from bacteria in a GBP1-dependent manner, promoting caspase-4 activation and pyroptosis.\",\n      \"method\": \"Shigella effector mutants, GBP1 CRISPR knockout, LPS quantification, caspase-4 activity and pyroptosis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with bacterial effector mutants and host CRISPR KO, mechanistic pathway defined\",\n      \"pmids\": [\"37014865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIM1 kinase phosphorylates GBP1, leading to its sequestration by 14-3-3σ, which prevents GBP1 membrane association; IFN-γ induces PIM1 expression, protecting macrophages from GBP1-mediated self-damage; during Toxoplasma infection, the parasite virulence protein TgIST depletes PIM1, increasing GBP1 activity for antimicrobial defense.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, PIM1 overexpression/knockdown, 14-3-3σ pulldown, TgIST-expressing parasites, macrophage viability assays, membrane fractionation\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical demonstration of phosphorylation and sequestration, mechanistically linked to cellular protection, multiple orthogonal approaches\",\n      \"pmids\": [\"37797010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Native cryo-electron tomography of human cells resolved the structure of a massive GBP1 defense complex polymerizing ~30,000 GBP molecules over the surface of gram-negative bacteria; construction requires GTP hydrolysis; GBP1 adopts an extended 'open conformer' for bacterial membrane insertion, establishing a platform that recruits caspase-4 and Gasdermin D; the assembled complex triggers LPS release that activates coassembled caspase-4.\",\n      \"method\": \"Cryo-electron tomography of infected human cells, GBP1 mutant analysis, quantitative imaging of complex assembly kinetics\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — native structural determination by cryo-ET combined with functional validation, foundational mechanism study\",\n      \"pmids\": [\"38422126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of soluble and membrane-bound GBP1 oligomers reveal that GBP1 assembles in an outstretched dimeric conformation; a surface-exposed helix in the large GTPase domain contributes to the oligomerization interface; nucleotide-dependent conformational changes coordinate dimerization, oligomerization, and membrane binding to allow pathogen encapsulation.\",\n      \"method\": \"Cryo-electron microscopy of soluble and membrane-bound GBP1 oligomers, mutagenesis of oligomerization interface helix, nucleotide-binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structures with mutagenesis validation of oligomerization mechanism\",\n      \"pmids\": [\"38267655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human GBP1 is recruited to damaged phagosomes/endolysosomes in a GTP-binding and isoprenylation-dependent manner; in vitro lipid-binding assays demonstrate direct binding of GBP1 to PI4P and PI(3,4)P2; live-cell imaging shows GBP1 mediates endolysosomal repair after membrane damage caused by intracellular mycobacteria.\",\n      \"method\": \"In vitro lipid-binding assay, live-cell imaging, GTP-binding and isoprenylation-deficient mutants, endolysosomal integrity assays, siRNA knockdown\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct lipid binding in vitro combined with cell-based imaging, single lab\",\n      \"pmids\": [\"37298652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GBP1 incorporates into microtubules via class III β-tubulin and binds the pro-survival kinase PIM1; inhibition of the GBP1:PIM1 interaction by NSC756093 was confirmed by surface plasmon resonance; mutagenesis and modeling identified the binding site at the interface of the helical and LG domains of GBP1.\",\n      \"method\": \"Surface plasmon resonance, molecular modeling, site-directed mutagenesis, NCI-60 cell panel screening\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct binding assay (SPR) with mutagenesis, functional link to drug resistance, single lab\",\n      \"pmids\": [\"25211704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GBP1 interacts with phosphoglycerate kinase 1 (PGK1) as confirmed by co-immunoprecipitation and mass spectrometry; GBP1 regulates epithelial-mesenchymal transition (EMT) through PGK1, promoting erlotinib resistance in non-small cell lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, GBP1 overexpression/knockdown, rescue experiment with PGK1\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP confirmed interaction with functional rescue, single lab\",\n      \"pmids\": [\"32582960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GBP1 promotes mitochondrial fission in glioblastoma cells by facilitating movement of Drp1 from the cytosol to the mitochondria; GBP1 co-localizes with Drp1 specifically at mitochondria; elevated GBP1 produces shorter and wider mitochondria consistent with fission; GBP1-mediated fission contributes to cell migration.\",\n      \"method\": \"Subcellular fractionation, co-localization imaging, Drp1 inhibitor (Mdivi-1) experiments, mitochondrial morphology analysis, migration assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — fractionation and imaging with functional migration readout, single lab\",\n      \"pmids\": [\"39457021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP1 is recruited to actin-rich pedestals induced by extracellular EPEC/EHEC bacteria in a manner independent of direct LPS contact; GBP1 recruitment is driven by pathogen-induced actin remodeling (demonstrated by FcγR-Tir chimeric receptor with sterile actin pedestals); GBP1-dependent caspase-4 trafficking to pedestals leads to pyroptosis and IL-18 release.\",\n      \"method\": \"Live-cell imaging, chimeric receptor engineering (FcγR-Tir), IgG-coated bead actin pedestal assay, caspase-4 recruitment and pyroptosis assays, in vivo mouse colonocyte imaging\",\n      \"journal\": \"bioRxiv / mBio (PMID:41040234)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel chimeric receptor reconstitution experiment establishing LPS-independent GBP1 recruitment mechanism, peer-reviewed version also exists\",\n      \"pmids\": [\"41040234\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human GBP1 is an IFN-γ-inducible large GTPase that, upon GTP hydrolysis, assembles into higher-order polymers and forms a microcapsule/coatomer on cytosolic gram-negative bacteria by directly binding LPS (including lipid A) through electrostatic interactions; this GBP1 coat nucleates recruitment of GBP2–4, caspase-4, and Gasdermin D to create an innate immune signaling platform that triggers caspase-4 activation, LPS release, and pyroptosis (non-canonical inflammasome), while simultaneously disrupting bacterial actin-based motility; GBP1 is also recruited to damaged pathogen-containing vacuoles (promoting rupture and release of microbial ligands for inflammasome detection) and to lipid PI4P-containing damaged endolysosomes (mediating repair); its membrane association and activity are restrained by PIM1 kinase-mediated phosphorylation and subsequent sequestration by 14-3-3σ; in non-immune contexts, GBP1 inhibits cell proliferation via its C-terminal helical domain (α9-helix) by directly binding the TEAD transcription factor and suppressing Hippo pathway target genes, independent of GTPase activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GBP1 is an interferon-γ-inducible large GTPase that functions as a central effector of cell-autonomous innate immunity against intracellular pathogens while also regulating cell proliferation through a GTPase-independent mechanism. Upon GTP hydrolysis, GBP1 polymerizes into massive coatomer assemblies (~30,000 molecules) on the surface of cytosolic Gram-negative bacteria by directly binding LPS through electrostatic interactions, disrupting the O-antigen barrier to unmask lipid A, and nucleating sequential recruitment of GBP2–4, caspase-4, and Gasdermin D to activate non-canonical inflammasome signaling and pyroptosis [PMID:32510692, PMID:32581219, PMID:38422126]. GBP1 also promotes rupture of pathogen-containing vacuoles to expose microbial ligands (DNA, LPS) for inflammasome detection, with its membrane association restrained by PIM1 kinase-mediated phosphorylation and 14-3-3σ sequestration [PMID:31268602, PMID:37797010]. Independent of its GTPase activity, GBP1 inhibits cell proliferation through its C-terminal α9-helix, which directly binds the TEAD transcription factor to suppress Hippo pathway target gene expression [PMID:30120107].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that GBP1 is not merely an IFN-induced bystander but an active antiviral effector: overexpression conferred resistance to VSV and EMCV, and antisense knockdown partially abrogated IFN-mediated protection, proving GBP1 contributes directly to the interferon antiviral state.\",\n      \"evidence\": \"Stable transfection (overexpression and antisense knockdown) of HeLa cells with viral infection assays\",\n      \"pmids\": [\"10087221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Antiviral mechanism not identified at the molecular level\", \"No demonstration against intracellular bacteria\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Revealing a second, non-immune function: GBP1 mediates the anti-proliferative effect of inflammatory cytokines on endothelial cells through its C-terminal helical domain, independent of GTPase activity and isoprenylation, separating its proliferation-suppressive and immune effector functions.\",\n      \"evidence\": \"Overexpression/knockdown in endothelial cells with domain deletion and GTPase-dead mutant analysis\",\n      \"pmids\": [\"11598000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target of the C-terminal domain unknown at this point\", \"Mechanism of proliferation inhibition unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining a signaling pathway for GBP1's anti-proliferative activity: GBP1 suppresses β-catenin/TCF signaling through a non-canonical mechanism independent of GSK-3β or proteasomal degradation, providing the first pathway-level explanation for proliferation inhibition.\",\n      \"evidence\": \"GBP1 overexpression/knockdown in intestinal epithelial cells with β-catenin/TCF reporter and phosphorylation assays\",\n      \"pmids\": [\"22692453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to β-catenin not demonstrated\", \"Relationship to C-terminal helical domain not tested\", \"Single laboratory study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that GBP1 functions in cell-autonomous anti-parasitic defense: mouse Gbp1 is recruited to Toxoplasma parasitophorous vacuoles in an IFN-γ-dependent manner, and Gbp1-knockout mice show impaired parasite control, establishing GBP1 as essential for anti-Toxoplasma immunity.\",\n      \"evidence\": \"Gbp1−/− mice and macrophages, parasite virulence factor mutants, genetic epistasis with Atg5\",\n      \"pmids\": [\"23633952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of vacuolar targeting and disruption unknown\", \"Mouse Gbp1 may not fully recapitulate human GBP1 biology\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying GBP1 as unique among human GBPs in directly coating cytosolic Gram-negative bacteria: a C-terminal triple-arginine motif mediates bacterial targeting, GBP1 recruits other GBP paralogs, and bacterial coating blocks actin-based motility by interfering with IcsA, revealing GBP1 as the initiator of a multi-GBP antimicrobial platform.\",\n      \"evidence\": \"siRNA knockdown, paralog overexpression, triple-arginine mutagenesis, actin tail and cell-to-cell spread assays in Shigella/Burkholderia infection\",\n      \"pmids\": [\"29233899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct LPS binding not yet demonstrated biochemically\", \"Downstream signaling consequences of the coat not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolving the direct molecular target of GBP1's anti-proliferative C-terminal domain: the α9-helix binds the DNA-binding domain of TEAD via a specific seven-residue motif (376VDHLFQK382), suppressing Hippo pathway transcriptional output independent of GTPase activity, unifying the 2001 domain-mapping with a defined target.\",\n      \"evidence\": \"Protein-binding assays, site-directed mutagenesis of GBP1 α9-helix, TEAD reporter assays, cell proliferation assays\",\n      \"pmids\": [\"30120107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GBP1–TEAD interaction not resolved at atomic level\", \"In vivo relevance of TEAD inhibition in tissues not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placing GBP1 upstream of inflammasome activation across two pathogens: GBP1 promotes Toxoplasma vacuole disruption and AIM2-dependent detection of parasite DNA while facilitating caspase-4 recruitment to Salmonella, establishing GBP1 as a general gateway for pathogen ligand exposure to cytosolic sensors.\",\n      \"evidence\": \"CRISPR/siRNA knockdown, GTPase-dead and prenylation-deficient mutants, inflammasome component knockouts in human macrophages\",\n      \"pmids\": [\"31268602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GBP1 physically disrupts vacuolar membranes not defined\", \"Whether GBP1 directly activates or merely presents ligands to caspase-4 unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing the biochemical basis of the GBP1 antimicrobial coat: GBP1 directly binds LPS with high affinity through electrostatic interactions, polymerizes on bacterial surfaces to disrupt the O-antigen barrier and unmask lipid A, and nucleates sequential GBP2–4 and caspase-4 recruitment, defining the non-canonical inflammasome signaling platform at the bacterial surface.\",\n      \"evidence\": \"In vitro LPS-binding assays, protein polymerization assays, CRISPR knockouts of individual GBPs, live-cell imaging, electron microscopy\",\n      \"pmids\": [\"32581219\", \"32510692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LPS recognition unresolved\", \"Stoichiometry of the GBP1–caspase-4 complex unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealing a feedback control circuit: caspase-1 cleaves GBP1 at D192, inactivating it; a cleavage-resistant D192E mutant enhances caspase-4-driven pyroptosis, showing that inflammasome activation self-limits GBP1 coat function to prevent excessive host cell death.\",\n      \"evidence\": \"GBP1-D192E mutagenesis, caspase activity assays, cryo-EM of vacuoles, cell death assays\",\n      \"pmids\": [\"32783936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other caspases also cleave GBP1 not tested\", \"Physiological significance of this feedback in vivo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extending GBP1 antimicrobial function to Legionella: GBP1 promotes rupture of Legionella-containing vacuoles in a T4SS-dependent manner, broadening GBP1's vacuole-disruption role beyond Toxoplasma to multiple intravacuolar pathogens.\",\n      \"evidence\": \"CRISPR/siRNA knockdown, LCV integrity assays, inflammasome activation in human macrophages\",\n      \"pmids\": [\"37737612\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of GBP1-mediated vacuole disruption still unknown\", \"Single laboratory finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining the regulatory mechanism that prevents GBP1 self-damage: PIM1 kinase phosphorylates GBP1, causing 14-3-3σ sequestration and preventing membrane association; IFN-γ induces PIM1 for host protection, while Toxoplasma virulence factor TgIST depletes PIM1 to unleash GBP1, establishing phosphorylation as the master switch controlling GBP1 activity.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphorylation assays, PIM1 overexpression/knockdown, 14-3-3σ pulldown, TgIST parasite experiments, membrane fractionation\",\n      \"pmids\": [\"37797010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation site(s) on GBP1 not fully mapped\", \"Whether other kinases also regulate GBP1 membrane association unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that GBP1-mediated LPS aggregation in the cytosol, rather than bacterial coat assembly per se, is sufficient for caspase-4 activation: a triple-arginine mutant unable to target bacteria still rescues pyroptosis, redefining the minimal requirement for non-canonical inflammasome triggering.\",\n      \"evidence\": \"In vitro caspase-4 activation with recombinant GBP1, triple-arginine mutant in GBP1-KO cells, pyroptosis assays\",\n      \"pmids\": [\"37023136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LPS is released from bacteria into the cytosol for GBP1 aggregation not fully resolved\", \"Relative contribution of coat-dependent vs coat-independent mechanisms in physiological infection unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolving the structural architecture of the GBP1 defense complex at native resolution: cryo-electron tomography and cryo-EM revealed that ~30,000 GBP1 molecules assemble in an extended open-conformer dimeric state on bacterial membranes via GTP hydrolysis-dependent oligomerization, with a surface-exposed helix mediating the oligomerization interface, providing the structural blueprint for the antimicrobial coatomer.\",\n      \"evidence\": \"Native cryo-electron tomography of infected human cells, cryo-EM of soluble and membrane-bound oligomers, mutagenesis of oligomerization interface\",\n      \"pmids\": [\"38422126\", \"38267655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of GBP1 bound to LPS not available\", \"How conformational changes couple GTP hydrolysis to membrane insertion at the single-molecule level not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of GBP1 in complex with LPS and caspase-4, the precise phosphorylation sites mediating PIM1/14-3-3σ regulation, whether GBP1's anti-proliferative (TEAD-binding) and antimicrobial (LPS-binding) functions are coordinated or independent in tissues, and the in vivo relevance of GBP1 in human infection and tumor suppression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution GBP1–LPS co-structure\", \"No in vivo human genetic studies linking GBP1 loss to immunodeficiency\", \"Relationship between anti-proliferative and antimicrobial functions in physiological contexts untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [4, 17, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 6, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 5, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6, 17, 19]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 12, 19]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6, 7, 14, 15, 17]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 5, 7, 14, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 10, 16]}\n    ],\n    \"complexes\": [\n      \"GBP1 antimicrobial coatomer (GBP1/2/3/4)\",\n      \"Non-canonical inflammasome platform (GBP1/caspase-4/GSDMD)\"\n    ],\n    \"partners\": [\n      \"GBP2\",\n      \"GBP3\",\n      \"GBP4\",\n      \"CASP4\",\n      \"GSDMD\",\n      \"TEAD1\",\n      \"PIM1\",\n      \"YWHAS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}