{"gene":"GBP2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2003,"finding":"Gbp2 (yeast) is a shuttling poly(A)+ RNA-binding protein whose nuclear import depends on the receptor Mtr10 and the SR-specific kinase Sky1; deletion of MTR10 increases Gbp2 binding to poly(A)+ RNA in the cytoplasm, suggesting Mtr10 facilitates Gbp2 dissociation from mRNA upon cytoplasmic arrival. Nuclear export of Gbp2 is coupled to mRNA export and requires continuous RNA Pol II transcription and mRNA-export factors.","method":"Genetic deletion (mtr10Δ, sky1Δ), poly(A)+ RNA localization assays, nuclear export dependency experiments","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined localization phenotype, multiple deletion strains, single lab","pmids":["12634846"],"is_preprint":false},{"year":2004,"finding":"Yeast Gbp2 (and Hrb1) are specifically associated with the TREX complex and interact with Ctk1 (the kinase that phosphorylates the RNA Pol II CTD during elongation), leading to cotranscriptional recruitment of Gbp2 to nascent mRNA across actively transcribed gene lengths.","method":"Co-immunoprecipitation with TREX components, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RIP, and ChIP as orthogonal methods in one study; independently consistent with later structural work","pmids":["14769921"],"is_preprint":false},{"year":2007,"finding":"Transcriptional activation of the gbp2 gene (mammalian) requires both STAT1 and IRF1. STAT1 (phosphorylated at S727) recruits CBP and HDAC1 to the gbp2 promoter and drives histone H4 hyperacetylation to create transcriptionally competent chromatin; IRF1 subsequently associates and directly contacts RNA Pol II to initiate transcription. A STAT1-S727A mutant strongly reduces CBP recruitment, H4 hyperacetylation, and RNA Pol II association at the gbp2 promoter.","method":"ChIP in WT, stat1−/−, irf1−/− cells; STAT1-S727A point-mutant analysis; Co-IP of IRF1 with RNA Pol II","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — active-site mutagenesis (S727A), ChIP in multiple KO backgrounds, Co-IP, multiple orthogonal methods in one study","pmids":["17293456"],"is_preprint":false},{"year":1998,"finding":"Murine GBP-2 is prenylated via a C-terminal CaaX motif, preferentially incorporating the C-20 isoprenoid geranylgeraniol, as detected by [3H]mevalonate incorporation in COS cells; despite prenylation, mGBP-2 is primarily cytosolic.","method":"[3H]mevalonate metabolic labeling, subcellular fractionation","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical labeling with isoprenoid precursor, subcellular fractionation; single lab","pmids":["9858320"],"is_preprint":false},{"year":2011,"finding":"IRGM proteins (Irgm1, Irgm3) indirectly regulate the intracellular localization of Gbp2 via macroautophagy; in Irgm1/Irgm3-deficient or Atg5-deficient cells, Gbp2 accumulates in LC3+ and p62/Sqstm1+ autophagic compartments. Co-IP showed Irgm3 does NOT directly interact with Gbp2, indicating the regulation is indirect through autophagic flux.","method":"Immunofluorescence co-localization with LC3/p62, co-immunoprecipitation (negative result for direct Irgm3–Gbp2 interaction), Atg5-KO cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with genetic KO, orthogonal imaging and Co-IP; single lab","pmids":["21757726"],"is_preprint":false},{"year":2014,"finding":"Yeast Gbp2 (and Hrb1) bind pre-mRNAs and the spliceosome during splicing, acting as quality control surveillance factors that retain unspliced transcripts in the nucleus; they stabilize TRAMP complex binding to spliceosome-associated transcripts to target faulty RNAs to the nuclear exosome; upon splicing completion, they recruit the export receptor Mex67 to allow nuclear export of correctly spliced mRNAs.","method":"Genetic deletion (gbp2Δ, hrb1Δ) with in situ hybridization for unspliced pre-mRNA accumulation, RNA immunoprecipitation, co-immunoprecipitation with spliceosome/TRAMP/Mex67","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, Co-IP, pre-mRNA leakage assay), consistent pathway model, single lab with comprehensive functional validation","pmids":["24452287"],"is_preprint":false},{"year":2015,"finding":"NMR structures of Gbp2 RRM1 and RRM2 show preferential binding to RNA containing the GGUG core motif, with sequence selectivity residing in a non-canonical interface in RRM2 related to the SRSF1 pseudoRRM. The C-terminal RRM3 domain does not bind RNA/DNA due to N-terminal extensions blocking the canonical interface; instead, RRM3 is essential for interaction with the THO/TREX complex, and key residues for this interaction were identified. Genetic interaction: double deletion of gbp2 and tho2 shows synthetic phenotype, and preventing Gbp2–THO interaction partly suppresses gene expression defects caused by THO inactivation.","method":"NMR structure determination, RNA-binding assays, mutagenesis of key RRM3 residues, genetic epistasis (double deletion)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structures with functional validation, mutagenesis, RNA-binding assays, and genetic epistasis in one study","pmids":["26602689"],"is_preprint":false},{"year":2016,"finding":"The Toxoplasma gondii rhoptry pseudokinase ROP54, injected into the host cytoplasm and localizing to the parasitophorous vacuole membrane, specifically suppresses host GBP2 loading onto the parasitophorous vacuole (but not IRGb6 loading), thereby promoting parasite immune evasion. Loss of ROP54 results in substantially increased GBP2 deposition on the vacuole.","method":"ROP54 disruption in type II T. gondii, immunofluorescence quantification of GBP2 and IRGb6 loading on PVM, macrophage clearance assay, in vivo virulence assay","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic deletion with defined GBP2 localization phenotype, multiple readouts; single lab","pmids":["27303719"],"is_preprint":false},{"year":2018,"finding":"Murine Gbp2 is ubiquitinated in a Toxoplasma gondii infection-independent manner, as detected by mass spectrometry using the di-glycine remnant method in IFNγ-stimulated murine embryonic fibroblasts.","method":"Mass spectrometry-based di-glycine remnant proteomics in MEFs","journal":"BMC research notes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single MS experiment identifying ubiquitination; no writer/eraser identified; single lab","pmids":["29510761"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the yeast THO•Sub2 complex at 3.7 Å reveals the THO complex assembly around Tho2 and stabilizes Sub2 in a semi-open conformation. THO interacts with the SR-like protein Gbp2 through both its RS domain and RRM domains; cross-linking mass spectrometry shows extensive THO–Gbp2 contacts with RRM domains near the Tho2 C-terminal domain, supporting a model where THO serves as a landing pad to configure Gbp2 for loading onto mRNP.","method":"Cryo-EM structure determination (3.7 Å), cross-linking mass spectrometry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus orthogonal cross-linking MS; structural and biochemical validation in one study","pmids":["33787496"],"is_preprint":false},{"year":2021,"finding":"Yeast Gbp2 localizes to cytoplasmic stress granules upon heat shock and oxidative stress. Gbp2 directly binds the translation initiation factor eIF4G1 via its RGG motif; tethering Gbp2 to a reporter mRNA reduces its translation in vivo, and Gbp2 represses translation in in vitro translation systems in an RGG-motif-dependent manner. The RGG-motif deletion mutant is also defective in polysome association.","method":"Pull-down assays (Gbp2–eIF4G1 interaction), in vivo tethering reporter assay, in vitro translation assay, polysome fractionation, stress granule imaging","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro translation assay, direct pull-down, in vivo tethering, multiple orthogonal methods; single lab","pmids":["33910495"],"is_preprint":false},{"year":2021,"finding":"Yeast Gbp2 (and Hrb1) extend quality control to the cytoplasm: they inhibit translation of exported transcripts and recruit cytoplasmic degradation factors to support nonsense-mediated decay (NMD), thereby linking nuclear splicing surveillance to cytoplasmic NMD.","method":"Genetic deletion with NMD reporter assays, biochemical fractionation (review/synthesis of prior experimental work from the lab)","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — review-style synthesis paper citing prior experiments; mechanistic claims largely reiterate published data from same lab without new primary experiments described in abstract","pmids":["34681934"],"is_preprint":false},{"year":2023,"finding":"GBP2 (human) directly binds and aggregates free LPS through protein polymerization; recombinant polymerized GBP2 is sufficient to enhance LPS-induced caspase-4 activation in a reconstituted in vitro reaction, independent of direct bacterial surface binding. GBP2 cannot bind bacteria on its own but requires GBP1; nonetheless, LPS aggregation by GBP2 is sufficient to promote non-canonical inflammasome activation.","method":"In vitro LPS aggregation assay, reconstituted caspase-4 activation assay with recombinant proteins, GBP1KO cell complementation experiments, GBP1 triple-arginine motif mutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, mutagenesis (triple-Arg motif), in cellulo complementation; multiple orthogonal methods","pmids":["37023136"],"is_preprint":false},{"year":2020,"finding":"GBP2 promotes GBM cell migration and invasion through a GBP2→Stat3→fibronectin (FN1) signaling cascade: GBP2 induces FN1 expression at both mRNA and protein levels, Stat3 pathway inhibition blocks GBP2-driven FN1 induction and invasion, and FN1 is required for GBP2-promoted invasiveness in vitro and in vivo.","method":"RNA interference (GBP2 knockdown/overexpression), Stat3 inhibitor treatment, in vitro migration/invasion assay, mouse intracranial tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with pathway inhibitor rescue, in vivo validation; single lab","pmids":["32518375"],"is_preprint":false},{"year":2021,"finding":"GBP-2 (murine) inhibits breast cancer cell migration and invadosome formation by regulating Rho family GTPases downstream; GBP-2 expression is inversely correlated with aggressiveness in 4T1 vs. 67NR cells, and altered GBP-2 expression levels modulate migration and invadosome formation without affecting proliferation.","method":"GBP-2 expression alteration in 4T1/67NR cell lines, proliferation assay, migration assay, invadosome formation assay, Rho GTPase activity assessment","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined cellular phenotypes and pathway placement; single lab","pmids":["34830789"],"is_preprint":false},{"year":2022,"finding":"GBP2 facilitates glioma progression through direct interaction with KIF22, which regulates EGFR signaling; GBP2 depletion impairs proliferation and migration in glioma cells, while overexpression enhances these processes in vitro and in vivo.","method":"Co-immunoprecipitation (GBP2–KIF22 interaction), siRNA knockdown, overexpression, in vitro proliferation/migration assays, in vivo tumor model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct Co-IP identifying binding partner, loss/gain-of-function cellular phenotypes; single lab","pmids":["35436989"],"is_preprint":false},{"year":2022,"finding":"GBP2 promotes STAT1 phosphorylation by competing with SHP1 for binding to STAT1 in MSS colorectal cancer cells; reduced GBP2 expression inhibits antigen processing/presentation machinery and CXCL10/11 expression upon IFN-γ stimulation, and decreases CD8+ T cell migration.","method":"Co-immunoprecipitation (GBP2 vs. SHP1 competition for STAT1 binding), GBP2 knockout, Transwell CD8+ T cell migration assay, CXCL10/11 measurement","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP competition assay and KO with defined signaling and cellular phenotypes; single lab","pmids":["35383115"],"is_preprint":false},{"year":2023,"finding":"GBP2 in macrophage-derived exosomes (L-Exo) activates NLRP3 inflammasome signaling as a direct target in alveolar epithelial cells, inducing epithelial cell dysfunction and pyroptosis; GBP2 inhibition in vivo and in vitro reverses these effects, while GBP2 overexpression promotes them.","method":"GBP2 siRNA knockdown and overexpression in macrophages, exosome transfer to epithelial cells, NLRP3 inflammasome activation assay, in vivo ALI model","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss- and gain-of-function with defined pathway; mechanistic link to NLRP3 as 'direct target' not biochemically validated in abstract; single lab","pmids":["37812968"],"is_preprint":false},{"year":2023,"finding":"GBP2 promotes M1 macrophage polarization by activating the Notch1 signaling pathway in the context of diabetic nephropathy.","method":"GBP2 knockdown/overexpression in macrophages, Notch1 pathway analysis, M1 polarization markers, in vitro and in vivo validation","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement based on expression changes after KD/OE without direct biochemical linkage described in abstract","pmids":["37622120"],"is_preprint":false},{"year":2024,"finding":"GBP2 interacts directly with OTUD5 (a deubiquitinase), and this interaction promotes GPX4 ubiquitination and degradation, driving ferroptosis in pulmonary vascular endothelial cells. EV-packaged GBP2 from macrophages transfers this pro-ferroptotic activity to endothelial cells. The small molecule Plantainoside D binds GBP2 and inhibits the GBP2–OTUD5 interaction, reducing GPX4 ubiquitination.","method":"RNA interference, adeno-associated virus transfection, endothelial-specific Gpx4 KO mice, cellular thermal shift assay, molecular docking, Co-immunoprecipitation (GBP2–OTUD5), ubiquitination assay for GPX4","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic KO, CETSA for compound binding; multiple orthogonal methods; single lab","pmids":["40156957"],"is_preprint":false},{"year":2024,"finding":"In triple-negative breast cancer cells, GBP2 promotes autophagy by co-acting with ATG2 (fluorescence co-localization) and inhibiting the PI3K/AKT/mTOR pathway, thereby enhancing paclitaxel sensitivity; autophagy inhibition reverses GBP2-driven PTX sensitization.","method":"Lentiviral GBP2 overexpression, immunoblotting, transmission electron microscopy, fluorescence co-localization (GBP2–ATG2), PI3K/AKT/mTOR pathway analysis, autophagy inhibitor rescue experiment, mouse xenograft model","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization (not confirmed binding), pathway inhibition rescue; single lab; co-localization does not definitively establish direct interaction","pmids":["38334171"],"is_preprint":false},{"year":2025,"finding":"PD-related stress promotes GBP2 geranylgeranylation, driving its accumulation at mitochondria where it directly binds the mitophagy receptor NIX via its large GTPase domain; GBP2 then targets NIX for ubiquitin-proteasomal degradation, suppressing NIX-mediated mitophagy and promoting dopaminergic neuron apoptosis. Pharmacological inhibition of geranylgeranylation (GGTI298) attenuates MPTP-induced neurotoxicity. GBP2 knockdown neuroprotection is abolished by mitophagy inhibition or NIX knockdown, establishing a linear pathway.","method":"Co-immunoprecipitation (GBP2–NIX), domain mapping (large GTPase domain), ubiquitination/proteasomal degradation assay, GBP2 knockdown in vivo (MPTP mouse model) and in vitro, GGTI298 pharmacological treatment, NIX knockdown epistasis","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding (Co-IP with domain mapping), ubiquitination assay, genetic epistasis (NIX KD and mitophagy inhibitor rescue), in vivo pharmacological validation; multiple orthogonal methods in one study","pmids":["41570768"],"is_preprint":false},{"year":2025,"finding":"Upon IFN-γ stimulation, GBP2 undergoes phase separation through an intrinsically disordered region, forming condensates that sequester SHP1 and sustain STAT1 activation, thereby suppressing SLC7A11 and sensitizing tumor cells to ferroptotic death. GBP2 also increases HMGB1 release from ferroptotic cells to promote CD8+ T cell infiltration. Disrupting GBP2 phase separation impairs ferroptosis and weakens T cell-driven tumor control.","method":"Phase separation assays (IDR-dependent condensate formation), Co-IP (GBP2 sequesters SHP1), STAT1 phosphorylation analysis, SLC7A11 expression analysis, HMGB1 release assay, in vivo tumor model with T cell analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — phase separation mechanism with IDR mutant disruption, Co-IP, downstream signaling validation, and in vivo T cell functional readout; multiple orthogonal methods in one study","pmids":["41444224"],"is_preprint":false},{"year":2025,"finding":"ATF4 promotes tubular epithelial cell pyroptosis in drug-induced AKI by activating STAT1 phosphorylation; STAT1 then interacts with GBP2 to drive NLRP3 inflammasome activation. ATF4 suppression inhibits STAT1 phosphorylation and disrupts the STAT1–GBP2 interaction, attenuating NLRP3 activation and pyroptosis.","method":"Co-immunoprecipitation (STAT1–GBP2), luciferase reporter assay, ATF4 conditional KO mice, Western blotting, RNA sequencing","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying STAT1–GBP2 interaction, genetic KO with pathway readouts; single lab","pmids":["41563239"],"is_preprint":false},{"year":2025,"finding":"GBP2 suppresses MLV replication by inhibiting furin protease, which is required to cleave the viral envelope glycoprotein (Env) at the SU-TM cleavage site. GBP2 sensitivity and furin dependence are determined by the amino acid sequence at the SU-TM cleavage site; substitution of ecotropic Moloney cleavage site sequence with XMRV sequence confers resistance to both GBP2 and furin silencing, and the reverse substitution confers sensitivity.","method":"Furin silencing, GBP2 overexpression in MLV infection assay, cleavage site sequence substitution mutagenesis in Env","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of viral substrate cleavage site, furin KD epistasis; defines GBP2 mechanism via furin inhibition; single lab","pmids":["39337476"],"is_preprint":false},{"year":2025,"finding":"GBP2 directly binds GSDMD (gasdermin D), inhibiting its cleavage-dependent activation and preventing non-pyroptotic GSDMD-driven YAP nuclear translocation; nuclear YAP represses CXCL9/10/11 transcription and limits CD8+ T cell infiltration. GBP2 thus maintains YAP in its inactive cytoplasmic state and enhances immune surveillance.","method":"Co-immunoprecipitation (GBP2–GSDMD direct binding), GSDMD cleavage assays, YAP localization analysis, CXCL9/10/11 transcription assays, genetic and pharmacological GSDMD inhibition, patient samples and mouse models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP identifying GBP2–GSDMD interaction, downstream functional validation; single lab","pmids":["42115407"],"is_preprint":false},{"year":2025,"finding":"Scutellarin inhibits LPS-induced M1 macrophage polarization by downregulating GBP2, which suppresses JAK2/STAT3 signaling; co-immunoprecipitation and molecular docking confirm a direct interaction between GBP2 and STAT3. GBP2 knockdown reduces and overexpression enhances LPS-induced M1 polarization markers.","method":"Co-immunoprecipitation (GBP2–STAT3), molecular docking, GBP2 siRNA knockdown and overexpression, LPS-induced ALI mouse model, RNA-seq","journal":"Phytotherapy research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and molecular docking supporting interaction; single lab, pathway placement based on pharmacological inhibitor of GBP2 expression rather than direct mechanism","pmids":["40968089"],"is_preprint":false},{"year":2025,"finding":"Pro-apoptotic proteins Bak and Bax act as positive regulators that amplify the Gbp2-caspase-11 axis during pyroptosis induced by Vibrio vulnificus and Salmonella Typhimurium: Bak-/- and Bax-/- MEFs exhibit significantly reduced Gbp2 upregulation and caspase-11 activation, whereas MCL-1 overexpression does not affect Gbp2 expression or caspase-11 activation.","method":"Bak-/- and Bax-/- MEFs, MCL-1 overexpression, caspase-11 activation assay, LDH release assay, membrane integrity assay","journal":"Journal of microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO (Bak, Bax) with defined Gbp2 and caspase-11 phenotype; negative MCL-1 control strengthens interpretation; single lab","pmids":["41025249"],"is_preprint":false},{"year":2025,"finding":"GBP2 promotes nanovaccine-driven M1 macrophage polarization (TAM reprogramming) in ovarian cancer through the GBP2–Pin1–NFκB pathway: elevated GBP2 recruits Pin1, activating NFκB signaling, driving M1 polarization and tumor growth inhibition; targeting Gbp2 diminishes nanovaccine antitumor efficacy in vivo.","method":"RNA-seq, single-cell RNA-seq, mass spectrometry proteomics, GBP2 targeting in vivo, Pin1 recruitment assay","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway defined primarily by transcriptomics and proteomics; direct biochemical GBP2–Pin1 interaction not explicitly confirmed by Co-IP in abstract; single lab","pmids":["39985265"],"is_preprint":false},{"year":2026,"finding":"GBP2 promotes podocyte pyroptosis in lupus nephritis via the AIM2 pathway: Gbp2 knockdown reduces GSDMD, AIM2, Caspase-1 expression and IL-1β/IL-18 secretion, while overexpression aggravates these effects; pyroptosis suppression by Gbp2 knockdown is partially restored by concurrent AIM2 overexpression, establishing GBP2 upstream of AIM2-mediated pyroptosis.","method":"siRNA knockdown and overexpression of Gbp2, AIM2 overexpression rescue experiment, western blotting for pyroptosis markers, ELISA for IL-1β/IL-18","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis experiment (AIM2 rescue of Gbp2 KD), loss- and gain-of-function with defined pathway; single lab","pmids":["41855126"],"is_preprint":false}],"current_model":"GBP2 is an IFN-γ-inducible large GTPase with mechanistically established roles spanning mRNA surveillance/export (in yeast: cotranscriptional loading onto mRNPs via the TREX/THO complex through its RRM3 domain, splicing quality control via TRAMP recruitment and Mex67-dependent export, and cytoplasmic translation repression via RGG-motif binding to eIF4G1), innate immune defense (direct LPS aggregation via polymerization to activate caspase-4 non-canonical inflammasome; regulation of GBP2 localization by autophagic flux downstream of IRGM proteins; mitochondrial accumulation via geranylgeranylation where it binds and targets NIX for degradation to suppress mitophagy), and tumor biology (phase separation-mediated SHP1 sequestration to sustain STAT1 activation driving ferroptosis; competition with SHP1 for STAT1 binding; direct GSDMD binding to suppress non-pyroptotic YAP nuclear translocation; STAT1 interaction promoted by ATF4 to activate NLRP3 inflammasome; regulation of Rho GTPases to inhibit migration; and transcriptional activation of the GBP2 gene itself requiring sequential STAT1- and IRF1-dependent chromatin remodeling)."},"narrative":{"mechanistic_narrative":"GBP2 is an interferon-inducible large GTPase whose two best-evidenced roles are nuclear mRNA surveillance/export in yeast and cell-autonomous innate immune defense in mammals [PMID:24452287, PMID:37023136]. In yeast, Gbp2 is cotranscriptionally loaded onto nascent mRNPs: it associates with the TREX/THO complex and the elongation kinase Ctk1, and structural work shows its RRM1/RRM2 domains read a GGUG RNA motif while its non-RNA-binding RRM3 docks onto THO, which acts as a landing pad that configures Gbp2 for mRNP loading [PMID:14769921, PMID:26602689, PMID:33787496]. Once loaded, Gbp2 functions as a splicing quality-control factor that retains unspliced transcripts, stabilizes TRAMP-directed exosomal degradation of faulty RNAs, and recruits the export receptor Mex67 for correctly spliced messages, with its shuttling controlled by the import receptor Mtr10 and kinase Sky1 [PMID:12634846, PMID:24452287]. It extends repression into the cytoplasm by binding eIF4G1 through its RGG motif to inhibit translation and by localizing to stress granules [PMID:33910495]. In mammals, the gene is transcriptionally activated by sequential STAT1- and IRF1-dependent chromatin remodeling at its promoter, and the protein is geranylgeranylated via a C-terminal CaaX motif [PMID:17293456, PMID:9858320]. GBP2 drives the non-canonical inflammasome by directly polymerizing and aggregating free LPS to potentiate caspase-4 activation, and its intracellular localization is governed by autophagic flux downstream of IRGM proteins [PMID:37023136, PMID:21757726]. In tumor biology GBP2 undergoes IDR-dependent phase separation to sequester the phosphatase SHP1, sustaining STAT1 activation, suppressing SLC7A11 and sensitizing cells to ferroptosis [PMID:41444224], and competes with SHP1 for STAT1 binding to enhance IFN-γ responses [PMID:35383115]. Under Parkinsonian stress, geranylgeranylated GBP2 accumulates at mitochondria, binds the mitophagy receptor NIX via its large GTPase domain, and targets NIX for proteasomal degradation to suppress mitophagy [PMID:41570768]. Across multiple settings GBP2 also modulates inflammasome and pyroptosis pathways (NLRP3, AIM2, GSDMD) and Rho/STAT-dependent cancer cell migration [PMID:42115407, PMID:41563239, PMID:34830789].","teleology":[{"year":2003,"claim":"Established that yeast Gbp2 is a shuttling poly(A)+ RNA-binding protein whose nucleocytoplasmic cycling is coupled to mRNA export, defining it as an mRNP-associated trafficking factor rather than a static nuclear protein.","evidence":"Genetic deletion (mtr10Δ, sky1Δ) with poly(A)+ RNA localization and export-dependency assays in yeast","pmids":["12634846"],"confidence":"Medium","gaps":["Did not define the RNA sequence specificity","Mechanism of cargo loading onto nascent transcripts not addressed"]},{"year":2004,"claim":"Showed Gbp2 is recruited cotranscriptionally via the TREX complex and the CTD kinase Ctk1, linking its mRNP loading to active transcription elongation.","evidence":"Co-IP with TREX components, RIP, and ChIP across transcribed genes in yeast","pmids":["14769921"],"confidence":"High","gaps":["Domain responsible for THO/TREX contact not yet mapped","Functional consequence for the loaded mRNA not defined"]},{"year":2007,"claim":"Defined how the mammalian gbp2 gene is induced, showing a two-step STAT1-then-IRF1 chromatin-remodeling mechanism that licenses transcription.","evidence":"ChIP in stat1−/− and irf1−/− cells, STAT1-S727A mutant, and IRF1–Pol II Co-IP","pmids":["17293456"],"confidence":"High","gaps":["Does not address GBP2 protein function","Upstream signals beyond IFN-γ not explored"]},{"year":1998,"claim":"Demonstrated murine GBP-2 is geranylgeranylated through a C-terminal CaaX motif, identifying a lipid modification that would later prove decisive for membrane targeting.","evidence":"[3H]mevalonate metabolic labeling and subcellular fractionation in COS cells","pmids":["9858320"],"confidence":"Medium","gaps":["Functional role of prenylation not established at the time","Conditions driving membrane recruitment unknown"]},{"year":2014,"claim":"Established Gbp2 as a splicing quality-control surveillance factor that retains unspliced transcripts, directs faulty RNAs to the exosome via TRAMP, and licenses export of correct mRNAs via Mex67.","evidence":"Deletion strains with in situ hybridization for pre-mRNA leakage, RIP, and Co-IP with spliceosome/TRAMP/Mex67 in yeast","pmids":["24452287"],"confidence":"High","gaps":["How the splicing status is sensed molecularly not resolved","Generality across all intron-containing genes not quantified"]},{"year":2015,"claim":"Resolved the structural basis of Gbp2 function, showing RRM1/RRM2 bind a GGUG motif while RRM3 instead mediates THO/TREX docking, separating RNA recognition from complex assembly.","evidence":"NMR structures of RRM1/RRM2/RRM3, RNA-binding assays, mutagenesis, and gbp2/tho2 genetic epistasis in yeast","pmids":["26602689"],"confidence":"High","gaps":["Architecture of the full mRNP-bound complex not visualized","Coordination between RNA binding and THO docking in vivo not timed"]},{"year":2021,"claim":"Provided a structural model in which THO serves as a landing pad that configures Gbp2 for mRNP loading, integrating both its RS and RRM domains.","evidence":"3.7 Å cryo-EM of the THO•Sub2 complex with cross-linking mass spectrometry mapping THO–Gbp2 contacts","pmids":["33787496"],"confidence":"High","gaps":["Conformational changes upon Gbp2 release not captured","Transfer step from THO to mature mRNP not visualized"]},{"year":2021,"claim":"Extended Gbp2 function into the cytoplasm, showing it directly represses translation through eIF4G1 binding via its RGG motif and partitions into stress granules.","evidence":"eIF4G1 pull-down, in vivo tethering reporter, in vitro translation, polysome fractionation, and stress-granule imaging in yeast","pmids":["33910495"],"confidence":"Medium","gaps":["Selectivity for specific mRNAs unknown","Link between nuclear surveillance and cytoplasmic repression not mechanistically closed"]},{"year":2011,"claim":"Showed that mammalian Gbp2 intracellular localization is controlled indirectly by IRGM proteins through autophagic flux rather than direct binding.","evidence":"LC3/p62 co-localization in Irgm1/Irgm3- and Atg5-deficient cells with a negative Irgm3–Gbp2 Co-IP","pmids":["21757726"],"confidence":"Medium","gaps":["Direct autophagy machinery interactor not identified","Functional consequence of mislocalization for pathogen defense not quantified"]},{"year":2016,"claim":"Demonstrated GBP2 is targeted to pathogen-containing vacuoles and that a pathogen actively counteracts this, framing GBP2 as a cell-autonomous anti-parasite effector.","evidence":"ROP54 disruption in T. gondii with immunofluorescence of GBP2/IRGb6 PVM loading and virulence assays","pmids":["27303719"],"confidence":"Medium","gaps":["Molecular determinant of GBP2 vacuolar loading not defined","Mechanism by which ROP54 blocks loading unknown"]},{"year":2023,"claim":"Defined a direct biochemical mechanism for GBP2 in innate immunity: it polymerizes to aggregate free LPS and potentiate caspase-4 non-canonical inflammasome activation.","evidence":"In vitro LPS aggregation and reconstituted caspase-4 activation with recombinant proteins, plus GBP1KO complementation","pmids":["37023136"],"confidence":"High","gaps":["Structural basis of GBP2 polymerization not resolved","Relative contribution of GBP1 vs GBP2 in cells not fully partitioned"]},{"year":2025,"claim":"Established a mitochondrial role for prenylated GBP2: it binds the mitophagy receptor NIX and drives its proteasomal degradation, suppressing mitophagy and promoting neuronal apoptosis.","evidence":"Co-IP with domain mapping (large GTPase domain), ubiquitination assay, NIX-knockdown epistasis, and GGTI298 in an MPTP mouse model","pmids":["41570768"],"confidence":"High","gaps":["E3 ligase mediating NIX degradation not identified","Whether GTPase activity is required not tested"]},{"year":2025,"claim":"Showed GBP2 phase separation sequesters SHP1 to sustain STAT1 signaling and sensitize tumors to ferroptosis, linking a condensate mechanism to immune-driven tumor control.","evidence":"IDR-dependent condensate assays, SHP1 Co-IP, STAT1/SLC7A11/HMGB1 readouts, and in vivo T-cell tumor models","pmids":["41444224"],"confidence":"High","gaps":["Trigger for condensate dissolution not defined","Relationship to GBP2 GTPase or prenylation states unexplored"]},{"year":2025,"claim":"Identified direct GBP2–GSDMD binding that blocks non-pyroptotic GSDMD-driven YAP nuclear translocation, expanding GBP2 immune-surveillance roles into chemokine control.","evidence":"GBP2–GSDMD Co-IP, GSDMD cleavage and YAP localization assays, CXCL9/10/11 transcription, patient samples and mouse models","pmids":["42115407"],"confidence":"Medium","gaps":["Binding interface on GSDMD not mapped","How binding inhibits cleavage mechanistically not resolved"]},{"year":null,"claim":"It remains unresolved how GBP2's GTPase activity, prenylation, polymerization, and phase-separation behaviors are mechanistically coordinated to switch between its mRNA-surveillance, anti-pathogen, mitochondrial, and tumor-signaling functions.","evidence":"No single study in the corpus integrates these biochemical states","pmids":[],"confidence":"Low","gaps":["No unified structural/biochemical model across functions","Role of nucleotide state in mammalian functions untested","Substrate/partner determinants of context-specific behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[21]},{"term_id":"GO:0098772","term_label":"molecular function regulator 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Independently of its GTPase activity, acts as an inhibitor of various viruses infectivity, such as HIV-1, Zika and influenza A viruses, by inhibiting FURIN-mediated maturation of viral envelope proteins (PubMed:31091448)","subcellular_location":"Cytoplasmic vesicle membrane; Golgi apparatus membrane; Cytoplasm; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/P32456/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GBP2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GBP2","total_profiled":1310},"omim":[{"mim_id":"612468","title":"GUANYLATE-BINDING PROTEIN 7; GBP7","url":"https://www.omim.org/entry/612468"},{"mim_id":"612467","title":"GUANYLATE-BINDING PROTEIN 6; GBP6","url":"https://www.omim.org/entry/612467"},{"mim_id":"612466","title":"GUANYLATE-BINDING PROTEIN 4; GBP4","url":"https://www.omim.org/entry/612466"},{"mim_id":"611467","title":"GUANYLATE-BINDING PROTEIN 5: GBP5","url":"https://www.omim.org/entry/611467"},{"mim_id":"600413","title":"GUANYLATE-BINDING PROTEIN 3; GBP3","url":"https://www.omim.org/entry/600413"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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non-pyroptotic.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/42115407","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33667,"output_tokens":8300,"usd":0.112751,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17958,"output_tokens":4861,"usd":0.105658,"stage2_stop_reason":"end_turn"},"total_usd":0.218409,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Gbp2 (yeast) is a shuttling poly(A)+ RNA-binding protein whose nuclear import depends on the receptor Mtr10 and the SR-specific kinase Sky1; deletion of MTR10 increases Gbp2 binding to poly(A)+ RNA in the cytoplasm, suggesting Mtr10 facilitates Gbp2 dissociation from mRNA upon cytoplasmic arrival. Nuclear export of Gbp2 is coupled to mRNA export and requires continuous RNA Pol II transcription and mRNA-export factors.\",\n      \"method\": \"Genetic deletion (mtr10Δ, sky1Δ), poly(A)+ RNA localization assays, nuclear export dependency experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined localization phenotype, multiple deletion strains, single lab\",\n      \"pmids\": [\"12634846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yeast Gbp2 (and Hrb1) are specifically associated with the TREX complex and interact with Ctk1 (the kinase that phosphorylates the RNA Pol II CTD during elongation), leading to cotranscriptional recruitment of Gbp2 to nascent mRNA across actively transcribed gene lengths.\",\n      \"method\": \"Co-immunoprecipitation with TREX components, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RIP, and ChIP as orthogonal methods in one study; independently consistent with later structural work\",\n      \"pmids\": [\"14769921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Transcriptional activation of the gbp2 gene (mammalian) requires both STAT1 and IRF1. STAT1 (phosphorylated at S727) recruits CBP and HDAC1 to the gbp2 promoter and drives histone H4 hyperacetylation to create transcriptionally competent chromatin; IRF1 subsequently associates and directly contacts RNA Pol II to initiate transcription. A STAT1-S727A mutant strongly reduces CBP recruitment, H4 hyperacetylation, and RNA Pol II association at the gbp2 promoter.\",\n      \"method\": \"ChIP in WT, stat1−/−, irf1−/− cells; STAT1-S727A point-mutant analysis; Co-IP of IRF1 with RNA Pol II\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — active-site mutagenesis (S727A), ChIP in multiple KO backgrounds, Co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17293456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Murine GBP-2 is prenylated via a C-terminal CaaX motif, preferentially incorporating the C-20 isoprenoid geranylgeraniol, as detected by [3H]mevalonate incorporation in COS cells; despite prenylation, mGBP-2 is primarily cytosolic.\",\n      \"method\": \"[3H]mevalonate metabolic labeling, subcellular fractionation\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical labeling with isoprenoid precursor, subcellular fractionation; single lab\",\n      \"pmids\": [\"9858320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IRGM proteins (Irgm1, Irgm3) indirectly regulate the intracellular localization of Gbp2 via macroautophagy; in Irgm1/Irgm3-deficient or Atg5-deficient cells, Gbp2 accumulates in LC3+ and p62/Sqstm1+ autophagic compartments. Co-IP showed Irgm3 does NOT directly interact with Gbp2, indicating the regulation is indirect through autophagic flux.\",\n      \"method\": \"Immunofluorescence co-localization with LC3/p62, co-immunoprecipitation (negative result for direct Irgm3–Gbp2 interaction), Atg5-KO cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with genetic KO, orthogonal imaging and Co-IP; single lab\",\n      \"pmids\": [\"21757726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Gbp2 (and Hrb1) bind pre-mRNAs and the spliceosome during splicing, acting as quality control surveillance factors that retain unspliced transcripts in the nucleus; they stabilize TRAMP complex binding to spliceosome-associated transcripts to target faulty RNAs to the nuclear exosome; upon splicing completion, they recruit the export receptor Mex67 to allow nuclear export of correctly spliced mRNAs.\",\n      \"method\": \"Genetic deletion (gbp2Δ, hrb1Δ) with in situ hybridization for unspliced pre-mRNA accumulation, RNA immunoprecipitation, co-immunoprecipitation with spliceosome/TRAMP/Mex67\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, Co-IP, pre-mRNA leakage assay), consistent pathway model, single lab with comprehensive functional validation\",\n      \"pmids\": [\"24452287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NMR structures of Gbp2 RRM1 and RRM2 show preferential binding to RNA containing the GGUG core motif, with sequence selectivity residing in a non-canonical interface in RRM2 related to the SRSF1 pseudoRRM. The C-terminal RRM3 domain does not bind RNA/DNA due to N-terminal extensions blocking the canonical interface; instead, RRM3 is essential for interaction with the THO/TREX complex, and key residues for this interaction were identified. Genetic interaction: double deletion of gbp2 and tho2 shows synthetic phenotype, and preventing Gbp2–THO interaction partly suppresses gene expression defects caused by THO inactivation.\",\n      \"method\": \"NMR structure determination, RNA-binding assays, mutagenesis of key RRM3 residues, genetic epistasis (double deletion)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structures with functional validation, mutagenesis, RNA-binding assays, and genetic epistasis in one study\",\n      \"pmids\": [\"26602689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Toxoplasma gondii rhoptry pseudokinase ROP54, injected into the host cytoplasm and localizing to the parasitophorous vacuole membrane, specifically suppresses host GBP2 loading onto the parasitophorous vacuole (but not IRGb6 loading), thereby promoting parasite immune evasion. Loss of ROP54 results in substantially increased GBP2 deposition on the vacuole.\",\n      \"method\": \"ROP54 disruption in type II T. gondii, immunofluorescence quantification of GBP2 and IRGb6 loading on PVM, macrophage clearance assay, in vivo virulence assay\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic deletion with defined GBP2 localization phenotype, multiple readouts; single lab\",\n      \"pmids\": [\"27303719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Murine Gbp2 is ubiquitinated in a Toxoplasma gondii infection-independent manner, as detected by mass spectrometry using the di-glycine remnant method in IFNγ-stimulated murine embryonic fibroblasts.\",\n      \"method\": \"Mass spectrometry-based di-glycine remnant proteomics in MEFs\",\n      \"journal\": \"BMC research notes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single MS experiment identifying ubiquitination; no writer/eraser identified; single lab\",\n      \"pmids\": [\"29510761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the yeast THO•Sub2 complex at 3.7 Å reveals the THO complex assembly around Tho2 and stabilizes Sub2 in a semi-open conformation. THO interacts with the SR-like protein Gbp2 through both its RS domain and RRM domains; cross-linking mass spectrometry shows extensive THO–Gbp2 contacts with RRM domains near the Tho2 C-terminal domain, supporting a model where THO serves as a landing pad to configure Gbp2 for loading onto mRNP.\",\n      \"method\": \"Cryo-EM structure determination (3.7 Å), cross-linking mass spectrometry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus orthogonal cross-linking MS; structural and biochemical validation in one study\",\n      \"pmids\": [\"33787496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Gbp2 localizes to cytoplasmic stress granules upon heat shock and oxidative stress. Gbp2 directly binds the translation initiation factor eIF4G1 via its RGG motif; tethering Gbp2 to a reporter mRNA reduces its translation in vivo, and Gbp2 represses translation in in vitro translation systems in an RGG-motif-dependent manner. The RGG-motif deletion mutant is also defective in polysome association.\",\n      \"method\": \"Pull-down assays (Gbp2–eIF4G1 interaction), in vivo tethering reporter assay, in vitro translation assay, polysome fractionation, stress granule imaging\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro translation assay, direct pull-down, in vivo tethering, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"33910495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Gbp2 (and Hrb1) extend quality control to the cytoplasm: they inhibit translation of exported transcripts and recruit cytoplasmic degradation factors to support nonsense-mediated decay (NMD), thereby linking nuclear splicing surveillance to cytoplasmic NMD.\",\n      \"method\": \"Genetic deletion with NMD reporter assays, biochemical fractionation (review/synthesis of prior experimental work from the lab)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review-style synthesis paper citing prior experiments; mechanistic claims largely reiterate published data from same lab without new primary experiments described in abstract\",\n      \"pmids\": [\"34681934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GBP2 (human) directly binds and aggregates free LPS through protein polymerization; recombinant polymerized GBP2 is sufficient to enhance LPS-induced caspase-4 activation in a reconstituted in vitro reaction, independent of direct bacterial surface binding. GBP2 cannot bind bacteria on its own but requires GBP1; nonetheless, LPS aggregation by GBP2 is sufficient to promote non-canonical inflammasome activation.\",\n      \"method\": \"In vitro LPS aggregation assay, reconstituted caspase-4 activation assay with recombinant proteins, GBP1KO cell complementation experiments, GBP1 triple-arginine motif mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, mutagenesis (triple-Arg motif), in cellulo complementation; multiple orthogonal methods\",\n      \"pmids\": [\"37023136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GBP2 promotes GBM cell migration and invasion through a GBP2→Stat3→fibronectin (FN1) signaling cascade: GBP2 induces FN1 expression at both mRNA and protein levels, Stat3 pathway inhibition blocks GBP2-driven FN1 induction and invasion, and FN1 is required for GBP2-promoted invasiveness in vitro and in vivo.\",\n      \"method\": \"RNA interference (GBP2 knockdown/overexpression), Stat3 inhibitor treatment, in vitro migration/invasion assay, mouse intracranial tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with pathway inhibitor rescue, in vivo validation; single lab\",\n      \"pmids\": [\"32518375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP-2 (murine) inhibits breast cancer cell migration and invadosome formation by regulating Rho family GTPases downstream; GBP-2 expression is inversely correlated with aggressiveness in 4T1 vs. 67NR cells, and altered GBP-2 expression levels modulate migration and invadosome formation without affecting proliferation.\",\n      \"method\": \"GBP-2 expression alteration in 4T1/67NR cell lines, proliferation assay, migration assay, invadosome formation assay, Rho GTPase activity assessment\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined cellular phenotypes and pathway placement; single lab\",\n      \"pmids\": [\"34830789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GBP2 facilitates glioma progression through direct interaction with KIF22, which regulates EGFR signaling; GBP2 depletion impairs proliferation and migration in glioma cells, while overexpression enhances these processes in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (GBP2–KIF22 interaction), siRNA knockdown, overexpression, in vitro proliferation/migration assays, in vivo tumor model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct Co-IP identifying binding partner, loss/gain-of-function cellular phenotypes; single lab\",\n      \"pmids\": [\"35436989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GBP2 promotes STAT1 phosphorylation by competing with SHP1 for binding to STAT1 in MSS colorectal cancer cells; reduced GBP2 expression inhibits antigen processing/presentation machinery and CXCL10/11 expression upon IFN-γ stimulation, and decreases CD8+ T cell migration.\",\n      \"method\": \"Co-immunoprecipitation (GBP2 vs. SHP1 competition for STAT1 binding), GBP2 knockout, Transwell CD8+ T cell migration assay, CXCL10/11 measurement\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP competition assay and KO with defined signaling and cellular phenotypes; single lab\",\n      \"pmids\": [\"35383115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GBP2 in macrophage-derived exosomes (L-Exo) activates NLRP3 inflammasome signaling as a direct target in alveolar epithelial cells, inducing epithelial cell dysfunction and pyroptosis; GBP2 inhibition in vivo and in vitro reverses these effects, while GBP2 overexpression promotes them.\",\n      \"method\": \"GBP2 siRNA knockdown and overexpression in macrophages, exosome transfer to epithelial cells, NLRP3 inflammasome activation assay, in vivo ALI model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss- and gain-of-function with defined pathway; mechanistic link to NLRP3 as 'direct target' not biochemically validated in abstract; single lab\",\n      \"pmids\": [\"37812968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GBP2 promotes M1 macrophage polarization by activating the Notch1 signaling pathway in the context of diabetic nephropathy.\",\n      \"method\": \"GBP2 knockdown/overexpression in macrophages, Notch1 pathway analysis, M1 polarization markers, in vitro and in vivo validation\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement based on expression changes after KD/OE without direct biochemical linkage described in abstract\",\n      \"pmids\": [\"37622120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GBP2 interacts directly with OTUD5 (a deubiquitinase), and this interaction promotes GPX4 ubiquitination and degradation, driving ferroptosis in pulmonary vascular endothelial cells. EV-packaged GBP2 from macrophages transfers this pro-ferroptotic activity to endothelial cells. The small molecule Plantainoside D binds GBP2 and inhibits the GBP2–OTUD5 interaction, reducing GPX4 ubiquitination.\",\n      \"method\": \"RNA interference, adeno-associated virus transfection, endothelial-specific Gpx4 KO mice, cellular thermal shift assay, molecular docking, Co-immunoprecipitation (GBP2–OTUD5), ubiquitination assay for GPX4\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic KO, CETSA for compound binding; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"40156957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In triple-negative breast cancer cells, GBP2 promotes autophagy by co-acting with ATG2 (fluorescence co-localization) and inhibiting the PI3K/AKT/mTOR pathway, thereby enhancing paclitaxel sensitivity; autophagy inhibition reverses GBP2-driven PTX sensitization.\",\n      \"method\": \"Lentiviral GBP2 overexpression, immunoblotting, transmission electron microscopy, fluorescence co-localization (GBP2–ATG2), PI3K/AKT/mTOR pathway analysis, autophagy inhibitor rescue experiment, mouse xenograft model\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization (not confirmed binding), pathway inhibition rescue; single lab; co-localization does not definitively establish direct interaction\",\n      \"pmids\": [\"38334171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PD-related stress promotes GBP2 geranylgeranylation, driving its accumulation at mitochondria where it directly binds the mitophagy receptor NIX via its large GTPase domain; GBP2 then targets NIX for ubiquitin-proteasomal degradation, suppressing NIX-mediated mitophagy and promoting dopaminergic neuron apoptosis. Pharmacological inhibition of geranylgeranylation (GGTI298) attenuates MPTP-induced neurotoxicity. GBP2 knockdown neuroprotection is abolished by mitophagy inhibition or NIX knockdown, establishing a linear pathway.\",\n      \"method\": \"Co-immunoprecipitation (GBP2–NIX), domain mapping (large GTPase domain), ubiquitination/proteasomal degradation assay, GBP2 knockdown in vivo (MPTP mouse model) and in vitro, GGTI298 pharmacological treatment, NIX knockdown epistasis\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding (Co-IP with domain mapping), ubiquitination assay, genetic epistasis (NIX KD and mitophagy inhibitor rescue), in vivo pharmacological validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"41570768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Upon IFN-γ stimulation, GBP2 undergoes phase separation through an intrinsically disordered region, forming condensates that sequester SHP1 and sustain STAT1 activation, thereby suppressing SLC7A11 and sensitizing tumor cells to ferroptotic death. GBP2 also increases HMGB1 release from ferroptotic cells to promote CD8+ T cell infiltration. Disrupting GBP2 phase separation impairs ferroptosis and weakens T cell-driven tumor control.\",\n      \"method\": \"Phase separation assays (IDR-dependent condensate formation), Co-IP (GBP2 sequesters SHP1), STAT1 phosphorylation analysis, SLC7A11 expression analysis, HMGB1 release assay, in vivo tumor model with T cell analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phase separation mechanism with IDR mutant disruption, Co-IP, downstream signaling validation, and in vivo T cell functional readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"41444224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF4 promotes tubular epithelial cell pyroptosis in drug-induced AKI by activating STAT1 phosphorylation; STAT1 then interacts with GBP2 to drive NLRP3 inflammasome activation. ATF4 suppression inhibits STAT1 phosphorylation and disrupts the STAT1–GBP2 interaction, attenuating NLRP3 activation and pyroptosis.\",\n      \"method\": \"Co-immunoprecipitation (STAT1–GBP2), luciferase reporter assay, ATF4 conditional KO mice, Western blotting, RNA sequencing\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying STAT1–GBP2 interaction, genetic KO with pathway readouts; single lab\",\n      \"pmids\": [\"41563239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP2 suppresses MLV replication by inhibiting furin protease, which is required to cleave the viral envelope glycoprotein (Env) at the SU-TM cleavage site. GBP2 sensitivity and furin dependence are determined by the amino acid sequence at the SU-TM cleavage site; substitution of ecotropic Moloney cleavage site sequence with XMRV sequence confers resistance to both GBP2 and furin silencing, and the reverse substitution confers sensitivity.\",\n      \"method\": \"Furin silencing, GBP2 overexpression in MLV infection assay, cleavage site sequence substitution mutagenesis in Env\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of viral substrate cleavage site, furin KD epistasis; defines GBP2 mechanism via furin inhibition; single lab\",\n      \"pmids\": [\"39337476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP2 directly binds GSDMD (gasdermin D), inhibiting its cleavage-dependent activation and preventing non-pyroptotic GSDMD-driven YAP nuclear translocation; nuclear YAP represses CXCL9/10/11 transcription and limits CD8+ T cell infiltration. GBP2 thus maintains YAP in its inactive cytoplasmic state and enhances immune surveillance.\",\n      \"method\": \"Co-immunoprecipitation (GBP2–GSDMD direct binding), GSDMD cleavage assays, YAP localization analysis, CXCL9/10/11 transcription assays, genetic and pharmacological GSDMD inhibition, patient samples and mouse models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP identifying GBP2–GSDMD interaction, downstream functional validation; single lab\",\n      \"pmids\": [\"42115407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Scutellarin inhibits LPS-induced M1 macrophage polarization by downregulating GBP2, which suppresses JAK2/STAT3 signaling; co-immunoprecipitation and molecular docking confirm a direct interaction between GBP2 and STAT3. GBP2 knockdown reduces and overexpression enhances LPS-induced M1 polarization markers.\",\n      \"method\": \"Co-immunoprecipitation (GBP2–STAT3), molecular docking, GBP2 siRNA knockdown and overexpression, LPS-induced ALI mouse model, RNA-seq\",\n      \"journal\": \"Phytotherapy research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and molecular docking supporting interaction; single lab, pathway placement based on pharmacological inhibitor of GBP2 expression rather than direct mechanism\",\n      \"pmids\": [\"40968089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pro-apoptotic proteins Bak and Bax act as positive regulators that amplify the Gbp2-caspase-11 axis during pyroptosis induced by Vibrio vulnificus and Salmonella Typhimurium: Bak-/- and Bax-/- MEFs exhibit significantly reduced Gbp2 upregulation and caspase-11 activation, whereas MCL-1 overexpression does not affect Gbp2 expression or caspase-11 activation.\",\n      \"method\": \"Bak-/- and Bax-/- MEFs, MCL-1 overexpression, caspase-11 activation assay, LDH release assay, membrane integrity assay\",\n      \"journal\": \"Journal of microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO (Bak, Bax) with defined Gbp2 and caspase-11 phenotype; negative MCL-1 control strengthens interpretation; single lab\",\n      \"pmids\": [\"41025249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP2 promotes nanovaccine-driven M1 macrophage polarization (TAM reprogramming) in ovarian cancer through the GBP2–Pin1–NFκB pathway: elevated GBP2 recruits Pin1, activating NFκB signaling, driving M1 polarization and tumor growth inhibition; targeting Gbp2 diminishes nanovaccine antitumor efficacy in vivo.\",\n      \"method\": \"RNA-seq, single-cell RNA-seq, mass spectrometry proteomics, GBP2 targeting in vivo, Pin1 recruitment assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway defined primarily by transcriptomics and proteomics; direct biochemical GBP2–Pin1 interaction not explicitly confirmed by Co-IP in abstract; single lab\",\n      \"pmids\": [\"39985265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GBP2 promotes podocyte pyroptosis in lupus nephritis via the AIM2 pathway: Gbp2 knockdown reduces GSDMD, AIM2, Caspase-1 expression and IL-1β/IL-18 secretion, while overexpression aggravates these effects; pyroptosis suppression by Gbp2 knockdown is partially restored by concurrent AIM2 overexpression, establishing GBP2 upstream of AIM2-mediated pyroptosis.\",\n      \"method\": \"siRNA knockdown and overexpression of Gbp2, AIM2 overexpression rescue experiment, western blotting for pyroptosis markers, ELISA for IL-1β/IL-18\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis experiment (AIM2 rescue of Gbp2 KD), loss- and gain-of-function with defined pathway; single lab\",\n      \"pmids\": [\"41855126\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GBP2 is an IFN-γ-inducible large GTPase with mechanistically established roles spanning mRNA surveillance/export (in yeast: cotranscriptional loading onto mRNPs via the TREX/THO complex through its RRM3 domain, splicing quality control via TRAMP recruitment and Mex67-dependent export, and cytoplasmic translation repression via RGG-motif binding to eIF4G1), innate immune defense (direct LPS aggregation via polymerization to activate caspase-4 non-canonical inflammasome; regulation of GBP2 localization by autophagic flux downstream of IRGM proteins; mitochondrial accumulation via geranylgeranylation where it binds and targets NIX for degradation to suppress mitophagy), and tumor biology (phase separation-mediated SHP1 sequestration to sustain STAT1 activation driving ferroptosis; competition with SHP1 for STAT1 binding; direct GSDMD binding to suppress non-pyroptotic YAP nuclear translocation; STAT1 interaction promoted by ATF4 to activate NLRP3 inflammasome; regulation of Rho GTPases to inhibit migration; and transcriptional activation of the GBP2 gene itself requiring sequential STAT1- and IRF1-dependent chromatin remodeling).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GBP2 is an interferon-inducible large GTPase whose two best-evidenced roles are nuclear mRNA surveillance/export in yeast and cell-autonomous innate immune defense in mammals [#5, #12]. In yeast, Gbp2 is cotranscriptionally loaded onto nascent mRNPs: it associates with the TREX/THO complex and the elongation kinase Ctk1, and structural work shows its RRM1/RRM2 domains read a GGUG RNA motif while its non-RNA-binding RRM3 docks onto THO, which acts as a landing pad that configures Gbp2 for mRNP loading [#1, #6, #9]. Once loaded, Gbp2 functions as a splicing quality-control factor that retains unspliced transcripts, stabilizes TRAMP-directed exosomal degradation of faulty RNAs, and recruits the export receptor Mex67 for correctly spliced messages, with its shuttling controlled by the import receptor Mtr10 and kinase Sky1 [#0, #5]. It extends repression into the cytoplasm by binding eIF4G1 through its RGG motif to inhibit translation and by localizing to stress granules [#10]. In mammals, the gene is transcriptionally activated by sequential STAT1- and IRF1-dependent chromatin remodeling at its promoter, and the protein is geranylgeranylated via a C-terminal CaaX motif [#2, #3]. GBP2 drives the non-canonical inflammasome by directly polymerizing and aggregating free LPS to potentiate caspase-4 activation, and its intracellular localization is governed by autophagic flux downstream of IRGM proteins [#12, #4]. In tumor biology GBP2 undergoes IDR-dependent phase separation to sequester the phosphatase SHP1, sustaining STAT1 activation, suppressing SLC7A11 and sensitizing cells to ferroptosis [#22], and competes with SHP1 for STAT1 binding to enhance IFN-\\u03b3 responses [#16]. Under Parkinsonian stress, geranylgeranylated GBP2 accumulates at mitochondria, binds the mitophagy receptor NIX via its large GTPase domain, and targets NIX for proteasomal degradation to suppress mitophagy [#21]. Across multiple settings GBP2 also modulates inflammasome and pyroptosis pathways (NLRP3, AIM2, GSDMD) and Rho/STAT-dependent cancer cell migration [#25, #23, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that yeast Gbp2 is a shuttling poly(A)+ RNA-binding protein whose nucleocytoplasmic cycling is coupled to mRNA export, defining it as an mRNP-associated trafficking factor rather than a static nuclear protein.\",\n      \"evidence\": \"Genetic deletion (mtr10\\u0394, sky1\\u0394) with poly(A)+ RNA localization and export-dependency assays in yeast\",\n      \"pmids\": [\"12634846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the RNA sequence specificity\", \"Mechanism of cargo loading onto nascent transcripts not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed Gbp2 is recruited cotranscriptionally via the TREX complex and the CTD kinase Ctk1, linking its mRNP loading to active transcription elongation.\",\n      \"evidence\": \"Co-IP with TREX components, RIP, and ChIP across transcribed genes in yeast\",\n      \"pmids\": [\"14769921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain responsible for THO/TREX contact not yet mapped\", \"Functional consequence for the loaded mRNA not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined how the mammalian gbp2 gene is induced, showing a two-step STAT1-then-IRF1 chromatin-remodeling mechanism that licenses transcription.\",\n      \"evidence\": \"ChIP in stat1\\u2212/\\u2212 and irf1\\u2212/\\u2212 cells, STAT1-S727A mutant, and IRF1\\u2013Pol II Co-IP\",\n      \"pmids\": [\"17293456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address GBP2 protein function\", \"Upstream signals beyond IFN-\\u03b3 not explored\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated murine GBP-2 is geranylgeranylated through a C-terminal CaaX motif, identifying a lipid modification that would later prove decisive for membrane targeting.\",\n      \"evidence\": \"[3H]mevalonate metabolic labeling and subcellular fractionation in COS cells\",\n      \"pmids\": [\"9858320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of prenylation not established at the time\", \"Conditions driving membrane recruitment unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established Gbp2 as a splicing quality-control surveillance factor that retains unspliced transcripts, directs faulty RNAs to the exosome via TRAMP, and licenses export of correct mRNAs via Mex67.\",\n      \"evidence\": \"Deletion strains with in situ hybridization for pre-mRNA leakage, RIP, and Co-IP with spliceosome/TRAMP/Mex67 in yeast\",\n      \"pmids\": [\"24452287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the splicing status is sensed molecularly not resolved\", \"Generality across all intron-containing genes not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the structural basis of Gbp2 function, showing RRM1/RRM2 bind a GGUG motif while RRM3 instead mediates THO/TREX docking, separating RNA recognition from complex assembly.\",\n      \"evidence\": \"NMR structures of RRM1/RRM2/RRM3, RNA-binding assays, mutagenesis, and gbp2/tho2 genetic epistasis in yeast\",\n      \"pmids\": [\"26602689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Architecture of the full mRNP-bound complex not visualized\", \"Coordination between RNA binding and THO docking in vivo not timed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided a structural model in which THO serves as a landing pad that configures Gbp2 for mRNP loading, integrating both its RS and RRM domains.\",\n      \"evidence\": \"3.7 \\u00c5 cryo-EM of the THO\\u2022Sub2 complex with cross-linking mass spectrometry mapping THO\\u2013Gbp2 contacts\",\n      \"pmids\": [\"33787496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes upon Gbp2 release not captured\", \"Transfer step from THO to mature mRNP not visualized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended Gbp2 function into the cytoplasm, showing it directly represses translation through eIF4G1 binding via its RGG motif and partitions into stress granules.\",\n      \"evidence\": \"eIF4G1 pull-down, in vivo tethering reporter, in vitro translation, polysome fractionation, and stress-granule imaging in yeast\",\n      \"pmids\": [\"33910495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for specific mRNAs unknown\", \"Link between nuclear surveillance and cytoplasmic repression not mechanistically closed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that mammalian Gbp2 intracellular localization is controlled indirectly by IRGM proteins through autophagic flux rather than direct binding.\",\n      \"evidence\": \"LC3/p62 co-localization in Irgm1/Irgm3- and Atg5-deficient cells with a negative Irgm3\\u2013Gbp2 Co-IP\",\n      \"pmids\": [\"21757726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct autophagy machinery interactor not identified\", \"Functional consequence of mislocalization for pathogen defense not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated GBP2 is targeted to pathogen-containing vacuoles and that a pathogen actively counteracts this, framing GBP2 as a cell-autonomous anti-parasite effector.\",\n      \"evidence\": \"ROP54 disruption in T. gondii with immunofluorescence of GBP2/IRGb6 PVM loading and virulence assays\",\n      \"pmids\": [\"27303719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinant of GBP2 vacuolar loading not defined\", \"Mechanism by which ROP54 blocks loading unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a direct biochemical mechanism for GBP2 in innate immunity: it polymerizes to aggregate free LPS and potentiate caspase-4 non-canonical inflammasome activation.\",\n      \"evidence\": \"In vitro LPS aggregation and reconstituted caspase-4 activation with recombinant proteins, plus GBP1KO complementation\",\n      \"pmids\": [\"37023136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GBP2 polymerization not resolved\", \"Relative contribution of GBP1 vs GBP2 in cells not fully partitioned\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a mitochondrial role for prenylated GBP2: it binds the mitophagy receptor NIX and drives its proteasomal degradation, suppressing mitophagy and promoting neuronal apoptosis.\",\n      \"evidence\": \"Co-IP with domain mapping (large GTPase domain), ubiquitination assay, NIX-knockdown epistasis, and GGTI298 in an MPTP mouse model\",\n      \"pmids\": [\"41570768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating NIX degradation not identified\", \"Whether GTPase activity is required not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed GBP2 phase separation sequesters SHP1 to sustain STAT1 signaling and sensitize tumors to ferroptosis, linking a condensate mechanism to immune-driven tumor control.\",\n      \"evidence\": \"IDR-dependent condensate assays, SHP1 Co-IP, STAT1/SLC7A11/HMGB1 readouts, and in vivo T-cell tumor models\",\n      \"pmids\": [\"41444224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for condensate dissolution not defined\", \"Relationship to GBP2 GTPase or prenylation states unexplored\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified direct GBP2\\u2013GSDMD binding that blocks non-pyroptotic GSDMD-driven YAP nuclear translocation, expanding GBP2 immune-surveillance roles into chemokine control.\",\n      \"evidence\": \"GBP2\\u2013GSDMD Co-IP, GSDMD cleavage and YAP localization assays, CXCL9/10/11 transcription, patient samples and mouse models\",\n      \"pmids\": [\"42115407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface on GSDMD not mapped\", \"How binding inhibits cleavage mechanistically not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how GBP2's GTPase activity, prenylation, polymerization, and phase-separation behaviors are mechanistically coordinated to switch between its mRNA-surveillance, anti-pathogen, mitochondrial, and tumor-signaling functions.\",\n      \"evidence\": \"No single study in the corpus integrates these biochemical states\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural/biochemical model across functions\", \"Role of nucleotide state in mammalian functions untested\", \"Substrate/partner determinants of context-specific behavior unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 22]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [12, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 6, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 16, 25]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [22, 29]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 21]}\n    ],\n    \"complexes\": [\"TREX/THO complex\"],\n    \"partners\": [\"Mex67\", \"eIF4G1\", \"STAT1\", \"SHP1\", \"NIX\", \"GSDMD\", \"OTUD5\", \"KIF22\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}