{"gene":"GBP2","run_date":"2026-04-28T18:06:52","timeline":{"discoveries":[{"year":2004,"finding":"Gbp2 (yeast SR-like protein) is cotranscriptionally recruited to nascent mRNA via association with the TREX complex and interacts with Ctk1, a kinase that phosphorylates the CTD of RNA Pol II during elongation; Gbp2 associates with actively transcribed genes and is bound to their transcripts.","method":"Co-immunoprecipitation, RNA immunoprecipitation, chromatin immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and RNA-IP with multiple orthogonal methods, highly cited foundational paper","pmids":["14769921"],"is_preprint":false},{"year":2003,"finding":"Yeast Gbp2 is a shuttling poly(A)+ RNA-binding protein whose nuclear import depends on the receptor Mtr10 and the SR kinase Sky1; deletion of MTR10 shifts Gbp2 to the cytoplasm and increases its poly(A)+ RNA binding, indicating Mtr10 mediates dissociation of Gbp2 from mRNA in the cytoplasm; nuclear export of Gbp2 is coupled to mRNA export and requires RNA Pol II transcription.","method":"Genetic deletion, subcellular fractionation/localization, RNA-binding assay, overexpression toxicity assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and biochemical approaches establishing import receptor, kinase dependency, and functional consequence","pmids":["12634846"],"is_preprint":false},{"year":2007,"finding":"For IFN-γ-induced transcription of the gbp2 gene, STAT1 binds the promoter independently of IRF1 and recruits CBP/HDAC1 and drives histone H4 hyperacetylation; STAT1 S727 phosphorylation (in its transactivation domain) is required for CBP recruitment and RNA Pol II association; IRF1 binds subsequently and directly contacts RNA Pol II-containing complexes, being required for productive transcription initiation.","method":"ChIP in WT/stat1−/−/irf1−/− cells, STAT1-S727A mutant analysis, co-immunoprecipitation 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 — multiple genetic backgrounds, mutagenesis, and ChIP with functional readout; highly cited","pmids":["17293456"],"is_preprint":false},{"year":2014,"finding":"Yeast Gbp2 and Hrb1 act as mRNA surveillance/quality-control factors: they bind pre-mRNAs and the spliceosome during splicing, are required for stable binding of the TRAMP complex to spliceosome-associated transcripts (targeting faulty RNAs to the nuclear exosome), and upon completion of correct splicing recruit the export receptor Mex67 to allow nuclear export; their absence causes leakage of unspliced pre-mRNAs into the cytoplasm.","method":"RNA immunoprecipitation, genetic deletion with quantitative pre-mRNA export assay, co-immunoprecipitation with spliceosome/TRAMP components","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, clean KO phenotype with specific molecular mechanism defined","pmids":["24452287"],"is_preprint":false},{"year":2011,"finding":"IRGM proteins (Irgm1, Irgm3) indirectly regulate the intracellular localization of murine Gbp2 through modulation of autophagic flux; in the absence of Irgm1/Irgm3 or Atg5, Gbp2 accumulates in LC3+ and p62/Sqstm1+ autophagic compartments; Irgm3 does not directly co-immunoprecipitate with Gbp2 (unlike its interaction with Irgb6), indicating an indirect mechanism via autophagy regulation.","method":"Immunofluorescence co-localization, co-immunoprecipitation, Atg5-KO cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiments with functional context, but mechanism is indirect and inferred from autophagy perturbation","pmids":["21757726"],"is_preprint":false},{"year":1998,"finding":"Murine GBP-2 is prenylated via its 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":"Radiolabeled mevalonate incorporation assay, subcellular fractionation","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 1 — direct biochemical prenylation assay with localization data, single study","pmids":["9858320"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the yeast THO•Sub2 complex at 3.7 Å resolution reveals THO stabilizes a semi-open conformation of the Sub2 ATPase via Tho2 interactions; THO interacts with the SR-like protein Gbp2 through both its RS domain and RRM domains, with cross-linking mass spectrometry showing RRM domains of Gbp2 are proximal to the Tho2 C-terminal domain, suggesting THO serves as a landing pad to configure Gbp2 for mRNP loading.","method":"Cryo-EM structure determination, cross-linking mass spectrometry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with cross-linking MS validation","pmids":["33787496"],"is_preprint":false},{"year":2015,"finding":"NMR structures of Gbp2 RRM1 and RRM2 show they preferentially bind RNAs containing the core motif GGUG, 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 its N-terminal extension blocking the canonical binding interface, but instead mediates interaction with the THO/TREX complex; key residues in RRM3 essential for THO interaction were identified and genetic interaction with Tho2 was confirmed.","method":"NMR structure determination, RNA binding assays, mutagenesis, yeast genetic epistasis (double deletion synthetic phenotype)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — NMR structures with mutagenesis and genetic epistasis, multiple orthogonal methods","pmids":["26602689"],"is_preprint":false},{"year":2021,"finding":"Yeast Gbp2 localizes to cytoplasmic stress granules upon heat shock and oxidative stress, directly binds translation initiation factor eIF4G1 via its RGG motif (mapped to a region overlapping with another repressor Sbp1), and acts as a translation repressor: tethering Gbp2 to a reporter mRNA reduces its translation in vivo, and Gbp2 directly represses translation in vitro in an RGG-motif-dependent manner.","method":"Fluorescence imaging, pulldown assay, polysome fractionation, in vivo tethering assay, in vitro translation assay, RGG-motif deletion mutant","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution of translation repression plus multiple in vivo assays with mutagenesis","pmids":["33910495"],"is_preprint":false},{"year":2021,"finding":"Yeast Gbp2 (and Hrb1) continue quality control on exported transcripts in the cytoplasm: they support nonsense-mediated decay (NMD) by inhibiting translation and recruiting cytoplasmic degradation factors, thereby linking nuclear and cytoplasmic mRNA quality control.","method":"Genetic deletion with NMD reporter assays, functional epistasis analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — review/synthesis paper consolidating experimental results, functional assays described","pmids":["34681934"],"is_preprint":false},{"year":2023,"finding":"Human GBP2, like GBP1, directly binds and aggregates 'free' LPS through protein polymerization; supplementation of recombinant polymerized GBP2 to an in vitro reaction is sufficient to enhance LPS-induced caspase-4 activation; GBP2 overexpression can restore gram-negative-induced pyroptosis in GBP1-knockout cells without binding to the bacterial surface, establishing that LPS aggregation (not bacterial surface binding) is sufficient for non-canonical inflammasome activation.","method":"In vitro caspase-4 activation assay with recombinant protein, GBP1-KO cell complementation, LPS aggregation assay, protein polymerization assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with recombinant proteins plus cell-based genetic complementation","pmids":["37023136"],"is_preprint":false},{"year":2016,"finding":"The Toxoplasma gondii rhoptry pseudokinase ROP54 modulates host GBP2 loading onto the parasitophorous vacuole membrane; parasites lacking ROP54 show substantially increased GBP2 (but not IRGb6) loading onto the vacuole, indicating ROP54 specifically counteracts GBP2-mediated innate immune defense.","method":"Genetic deletion of ROP54 in T. gondii type II strain, immunofluorescence quantification of GBP2 loading, in vivo virulence assay, macrophage clearance assay","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic deletion with specific phenotypic readout of GBP2 loading","pmids":["27303719"],"is_preprint":false},{"year":2020,"finding":"In glioblastoma cells, GBP2 promotes cell migration and invasion via a GBP2/Stat3/fibronectin (FN1) signaling cascade: GBP2 overexpression induces FN1 at mRNA and protein levels, Stat3 pathway inhibition prevents GBP2-promoted FN1 induction and invasion, and GBP2 promotes tumor growth and invasion in mouse xenograft models.","method":"RNAi knockdown and overexpression, in vitro migration/invasion assays, Stat3 inhibitor, in vivo mouse tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD/OE with pharmacological pathway inhibition and in vivo validation, single lab","pmids":["32518375"],"is_preprint":false},{"year":2022,"finding":"Human GBP2 promotes STAT1 phosphorylation by competing with SHP1 for binding to STAT1 in microsatellite-stable colorectal cancer cells, enhancing antigen processing/presentation and CXCL10/11 expression upon IFN-γ stimulation.","method":"Co-immunoprecipitation (GBP2/SHP1/STAT1), GBP2 knockout, western blot for p-STAT1, cytokine measurement","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP establishing competitive binding plus KO functional phenotype, single lab","pmids":["35383115"],"is_preprint":false},{"year":2021,"finding":"GBP-2 (murine) inhibits migration and invadosome formation in breast cancer cells downstream of Rho GTPase regulation, without affecting proliferation; GBP-2 expression is inversely correlated with aggressiveness/metastasis in 4T1 vs. 67NR murine breast cancer cell lines.","method":"GBP-2 expression alteration, migration assays, invadosome formation assay, Rho GTPase activity measurement","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD/OE with specific cellular phenotype and pathway placement via Rho GTPase measurement","pmids":["34830789"],"is_preprint":false},{"year":2018,"finding":"Murine Gbp1 and Gbp2 are ubiquitinated independently of Toxoplasma gondii infection, as identified by mass spectrometry detection of di-glycine ubiquitin remnants on both proteins in IFNγ-stimulated MEFs.","method":"Mass spectrometry-based ubiquitinomics (di-glycine remnant profiling) in MEFs","journal":"BMC research notes","confidence":"Medium","confidence_rationale":"Tier 2 — direct MS identification of ubiquitination sites, but writer/eraser not identified","pmids":["29510761"],"is_preprint":false},{"year":2025,"finding":"In Parkinson's disease models, GBP2 undergoes geranylgeranylation (a prenylation modification) driving its accumulation at mitochondria, where it directly binds the mitophagy receptor NIX via its large GTPase domain and promotes NIX ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy and causing dopaminergic neuron loss; pharmacological inhibition of geranylgeranylation with GGTI298 attenuates MPTP-induced neurotoxicity.","method":"Co-immunoprecipitation (GBP2–NIX), GBP2 knockdown in vivo and in vitro, mitophagy assays, proteasome inhibitor rescue, NIX KD epistasis, GGTI298 pharmacological inhibition, MPTP mouse model","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding identified by Co-IP, domain mapping, epistasis with NIX KD, in vivo pharmacological validation","pmids":["41570768"],"is_preprint":false},{"year":2025,"finding":"GBP2 undergoes phase separation through an intrinsically disordered region upon IFN-γ stimulation, forming condensates that sequester SHP1 and sustain STAT1 activation; this enhances STAT1-driven suppression of SLC7A11, sensitizing melanoma tumor cells to ferroptosis; disrupting GBP2 phase separation impairs ferroptosis and tumor control by T cells.","method":"Phase separation assay, intrinsically disordered region mutagenesis, co-immunoprecipitation (GBP2–SHP1), western blot for p-STAT1/SLC7A11, HMGB1 release measurement, in vivo tumor growth assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — phase separation with mutagenesis, direct SHP1 sequestration by Co-IP, functional downstream pathway validation with in vivo confirmation","pmids":["41444224"],"is_preprint":false},{"year":2025,"finding":"EV-packaged GBP2 from macrophages directly binds OTUD5 (a deubiquitinase) and promotes GPX4 ubiquitination and degradation in pulmonary vascular endothelial cells, thereby driving ferroptosis and vascular barrier disruption in sepsis-associated lung injury; the small molecule Plantainoside D inhibits GBP2–OTUD5 interaction and reduces GPX4 ubiquitination.","method":"RNA interference, Co-IP (GBP2–OTUD5), AAV transfection, endothelial-specific Gpx4-KO mice, cellular thermal shift assay, molecular docking/dynamics, ubiquitination assay","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding by Co-IP, ubiquitination assay with KO validation, multiple orthogonal in vivo and in vitro methods","pmids":["40156957"],"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, western blot for Notch1 pathway markers, cytokine measurement","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pathway activation assay without direct binding partner identification","pmids":["37622120"],"is_preprint":false},{"year":2024,"finding":"GBP2 directly interacts with kinesin family member KIF22 in glioma cells and regulates EGFR signaling through the KIF22/EGFR axis to promote glioma cell proliferation and migration.","method":"Co-immunoprecipitation (GBP2–KIF22), GBP2 knockdown/overexpression, EGFR signaling western blot, in vitro proliferation/migration assays","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with KD/OE functional assay, single lab","pmids":["35436989"],"is_preprint":false},{"year":2024,"finding":"GBP2 inhibits pathological retinal angiogenesis by suppressing VEGFA expression and secretion through inhibition of the AKT/mTOR signaling pathway in retinal pigment epithelial cells and OIR mouse retinas.","method":"GBP2 silencing/overexpression, western blot for AKT/mTOR/VEGFA, VEGFA ELISA, conditioned medium angiogenesis assay with HUVECs, OIR mouse model","journal":"Microvascular research","confidence":"Low","confidence_rationale":"Tier 3 — KD/OE with pathway inhibition readout, no direct binding partner identified, single lab","pmids":["38636926"],"is_preprint":false},{"year":2025,"finding":"In silicosis, GBP2 in macrophages activates the c-Jun pathway to promote M2 macrophage polarization and inflammatory factor secretion; in epithelial cells, GBP2 promotes epithelial-mesenchymal transition (EMT) by upregulating the transcription factor KLF8.","method":"Western blot, RT-qPCR, GBP2 knockdown/overexpression, immunofluorescence in THP-1 cells and epithelial cells","journal":"Xi bao yu fen zi mian yi xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 — KD/OE with pathway markers, no direct binding demonstrated, single lab","pmids":["40620118"],"is_preprint":false},{"year":2026,"finding":"ATF4 (master regulator of integrated stress response) promotes GBP2 expression and phosphorylated STAT1 interaction with GBP2, leading to NLRP3 inflammasome activation and tubular epithelial cell pyroptosis in drug-induced AKI; ATF4 suppression disrupts STAT1–GBP2 interaction and attenuates pyroptosis.","method":"Single-cell RNA-seq, co-immunoprecipitation (STAT1–GBP2), luciferase reporter, ATF4-specific KO mice, western blotting, pharmacological ATF4 inhibition","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of STAT1–GBP2 complex with genetic KO and pharmacological validation, multiple methods","pmids":["41563239"],"is_preprint":false},{"year":2025,"finding":"GBP2 promotes podocyte pyroptosis in lupus nephritis via the AIM2 pathway: Gbp2 knockdown reduces GSDMD and AIM2 expression and decreases IL-1β/IL-18 secretion, while Gbp2 overexpression exacerbates these effects; the pyroptosis suppression from Gbp2 knockdown is partially restored by concurrent AIM2 overexpression.","method":"siRNA knockdown, overexpression, rescue experiment (AIM2 OE), western blot, cytokine ELISA, in vitro LPS/ATP podocyte pyroptosis model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic epistasis (rescue experiment) placing GBP2 upstream of AIM2 in pyroptosis pathway","pmids":["41855126"],"is_preprint":false},{"year":2025,"finding":"GBP2 suppresses MLV replication by inhibiting furin protease cleavage of the viral envelope glycoprotein SU-TM junction; the sensitivity of MLV Env to GBP2 and furin is determined by the amino acid sequence at the SU-TM cleavage site; substitution of the ecotropic cleavage site sequence with XMRV sequence confers resistance to GBP2, and vice versa.","method":"Furin silencing, cleavage site amino acid substitution mutagenesis, infection efficiency assay, western blot for Env cleavage","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 — site-directed mutagenesis of substrate cleavage site defining GBP2 mechanism of viral restriction","pmids":["39337476"],"is_preprint":false},{"year":2025,"finding":"In macrophages, GBP2 promotes M1 polarization and NF-κB pathway activation by recruiting Pin1; nanovaccine-enhanced Gbp2 expression drives TAM reprogramming to M1 phenotype through the Gbp2-Pin1-NFκB pathway.","method":"RNA-seq, scRNA-seq, mass spectrometry proteomics, GBP2 targeting in vivo","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 — Pin1 interaction identified by proteomics without direct binding validation, pathway inferred from omics","pmids":["39985265"],"is_preprint":false},{"year":2025,"finding":"GBP2 promotes non-canonical pyroptosis through the GBP2-caspase-11 axis during Vibrio vulnificus and Salmonella infections; pro-apoptotic proteins Bak and Bax act as positive regulators upstream of Gbp2 upregulation and caspase-11 activation, while anti-apoptotic MCL-1 does not affect this process.","method":"Bak-KO and Bax-KO MEFs, caspase-11 activation assay, LDH release, GBP2 western blot","journal":"Journal of microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis using KO cells placing Bak/Bax upstream of Gbp2 in pyroptosis pathway","pmids":["41025249"],"is_preprint":false}],"current_model":"GBP2 is an IFN-γ-inducible large GTPase with multiple mechanistic roles: in yeast, it is an SR-like shuttling protein recruited cotranscriptionally via the TREX/THO complex (whose interaction is mediated by its RRM3 domain) to perform nuclear mRNA quality control by surveilling splicing, recruiting TRAMP to defective transcripts, and loading Mex67 onto mature mRNAs for export, while also acting as a cytoplasmic translation repressor via RGG-motif-dependent eIF4G1 binding; in mammalian innate immunity, human GBP2 directly polymerizes free LPS and aggregates it to enhance caspase-4 activation, facilitates pyroptosis (including via the non-canonical caspase-11 axis and the AIM2/GSDMD axis), undergoes IFN-γ-induced phase separation through an intrinsically disordered region to sequester SHP1 and sustain STAT1 activation (thereby suppressing SLC7A11 and promoting ferroptosis), and upon geranylgeranylation-driven mitochondrial translocation directly binds the mitophagy receptor NIX via its GTPase domain to promote NIX degradation and impair mitophagy."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing the post-translational modification status of GBP2: murine GBP-2 was shown to be geranylgeranylated at its C-terminal CaaX motif yet remain primarily cytosolic, raising the question of what triggers its membrane relocalization.","evidence":"Radiolabeled mevalonate incorporation in COS cells with subcellular fractionation","pmids":["9858320"],"confidence":"Medium","gaps":["Stimulus or signal triggering membrane translocation was unknown","Whether prenylation is required for function was untested","Human GBP2 prenylation status not addressed"]},{"year":2003,"claim":"Defining yeast Gbp2 as a shuttling mRNA-binding protein whose nuclear-cytoplasmic transport depends on the import receptor Mtr10 and the SR kinase Sky1, establishing its identity as an SR-like protein coupled to mRNA export.","evidence":"Genetic deletion of MTR10, subcellular localization, poly(A)+ RNA binding assays in S. cerevisiae","pmids":["12634846"],"confidence":"High","gaps":["How Gbp2 is loaded onto mRNA in the nucleus was unknown","Functional consequence of Gbp2 shuttling for mRNA fate was not defined"]},{"year":2004,"claim":"Resolving how Gbp2 is recruited to mRNA: cotranscriptional loading via the TREX complex and association with the CTD kinase Ctk1 showed that Gbp2 joins nascent transcripts during elongation, not post-transcriptionally.","evidence":"Co-IP, RNA-IP, and ChIP on actively transcribed genes in S. cerevisiae","pmids":["14769921"],"confidence":"High","gaps":["Which domain of Gbp2 mediates TREX interaction was unresolved","Functional purpose of cotranscriptional loading (surveillance vs. export) was unclear"]},{"year":2007,"claim":"Defining the transcriptional regulation of the mammalian gbp2 gene: STAT1 S727 phosphorylation recruits CBP to the promoter, and IRF1 subsequently contacts RNA Pol II for productive transcription, establishing the two-step IFN-γ transcriptional activation mechanism.","evidence":"ChIP in WT, stat1−/−, and irf1−/− cells with STAT1-S727A mutagenesis","pmids":["17293456"],"confidence":"High","gaps":["Whether this promoter architecture is shared by other GBP family members was not tested","Post-transcriptional regulation of GBP2 mRNA was not addressed"]},{"year":2014,"claim":"Establishing yeast Gbp2 as a nuclear mRNA quality-control factor: Gbp2 binds pre-mRNAs on the spliceosome, recruits TRAMP to target faulty transcripts for exosome degradation, and upon correct splicing loads the export receptor Mex67, gating mRNA export on splicing fidelity.","evidence":"RNA-IP, co-IP with spliceosome/TRAMP components, quantitative pre-mRNA export assays in deletion strains","pmids":["24452287"],"confidence":"High","gaps":["How Gbp2 distinguishes correctly from incorrectly spliced transcripts at the molecular level was unclear","Whether Gbp2 surveils all intron-containing genes equally was not addressed"]},{"year":2015,"claim":"Structural basis of Gbp2 RNA recognition and TREX interaction: NMR structures revealed RRM1/2 bind GGUG-containing RNA while RRM3 does not bind RNA but instead mediates interaction with THO/TREX, resolving the domain-level division of labor.","evidence":"NMR structure determination, RNA binding assays, mutagenesis, genetic epistasis with Tho2 in S. cerevisiae","pmids":["26602689"],"confidence":"High","gaps":["Full atomic-resolution structure of the Gbp2–THO complex was lacking","How RRM3–THO interaction is released after mRNP remodeling was unknown"]},{"year":2016,"claim":"Demonstrating that mammalian GBP2 is recruited to pathogen-containing vacuoles and is actively counteracted by pathogen effectors: T. gondii ROP54 specifically limits GBP2 loading onto the parasitophorous vacuole.","evidence":"ROP54-KO T. gondii, quantitative immunofluorescence of GBP2 loading on vacuoles in macrophages","pmids":["27303719"],"confidence":"Medium","gaps":["Direct molecular target of ROP54 on GBP2 was not identified","Whether GBP2 vacuolar recruitment requires GTPase activity was untested"]},{"year":2021,"claim":"Cryo-EM of the THO•Sub2 complex confirmed that THO serves as a structural landing pad for Gbp2 loading, with cross-linking MS placing Gbp2 RRM domains near the Tho2 C-terminal domain, providing the first structural view of this interaction.","evidence":"Cryo-EM at 3.7 Å resolution with cross-linking mass spectrometry","pmids":["33787496"],"confidence":"High","gaps":["A co-structure of THO bound to full-length Gbp2 was not obtained","Dynamics of Gbp2 handoff from THO to mRNA were not resolved"]},{"year":2021,"claim":"Expanding Gbp2 beyond nuclear surveillance to cytoplasmic translation repression: Gbp2 localizes to stress granules, directly binds eIF4G1 via its RGG motif, and represses translation both in vivo and in vitro, linking its nuclear and cytoplasmic mRNA regulatory roles.","evidence":"In vitro translation repression assay, tethering assay, RGG-motif deletion, pulldown with eIF4G1 in S. cerevisiae","pmids":["33910495"],"confidence":"High","gaps":["Whether translation repression and stress granule localization are functionally separable was unclear","Physiological conditions activating cytoplasmic Gbp2 repression beyond heat shock were not fully defined"]},{"year":2022,"claim":"Revealing the mammalian GBP2–SHP1–STAT1 axis: GBP2 competes with phosphatase SHP1 for STAT1 binding, sustaining STAT1 phosphorylation and IFN-γ signaling in colorectal cancer cells.","evidence":"Co-IP of GBP2/SHP1/STAT1, GBP2 knockout, p-STAT1 western blot in microsatellite-stable CRC cells","pmids":["35383115"],"confidence":"Medium","gaps":["Binding interface between GBP2 and STAT1 was not mapped","Whether GBP2 GTPase activity is required for SHP1 displacement was untested"]},{"year":2023,"claim":"Demonstrating that human GBP2 directly polymerizes and aggregates free LPS to enhance caspase-4 activation, establishing a GBP1-independent mechanism for non-canonical inflammasome engagement that does not require bacterial surface binding.","evidence":"In vitro caspase-4 activation with recombinant GBP2, LPS aggregation assay, GBP1-KO cell complementation","pmids":["37023136"],"confidence":"High","gaps":["Structural basis of GBP2 polymerization on LPS was not resolved","Relative contributions of GBP2 vs. GBP1 to LPS sensing in physiological infection were not quantified"]},{"year":2025,"claim":"Multiple parallel advances defined new GBP2 effector mechanisms: (1) IFN-γ-induced phase separation via an intrinsically disordered region sequesters SHP1 to sustain STAT1 and drive ferroptosis; (2) geranylgeranylation drives mitochondrial translocation where GBP2 binds NIX and promotes its proteasomal degradation, impairing mitophagy in dopaminergic neurons; (3) GBP2 in macrophage-derived EVs binds OTUD5 to promote GPX4 ubiquitination and ferroptosis in endothelial cells; (4) GBP2 restricts MLV by inhibiting furin-mediated Env cleavage at the SU-TM junction.","evidence":"Phase separation/IDR mutagenesis with in vivo tumor models [PMID:41444224]; Co-IP of GBP2–NIX with GTPase domain mapping and MPTP mouse model [PMID:41570768]; Co-IP of GBP2–OTUD5 with GPX4 ubiquitination assay and endothelial-specific Gpx4-KO mice [PMID:40156957]; furin silencing and cleavage-site mutagenesis of MLV Env [PMID:39337476]","pmids":["41444224","41570768","40156957","39337476"],"confidence":"High","gaps":["Whether phase separation and LPS polymerization activities are coordinated in infection is unknown","The GBP2–OTUD5 interaction domain has not been mapped","Whether NIX binding requires GTP hydrolysis or only GTP binding is unresolved"]},{"year":2025,"claim":"GBP2 was placed upstream of multiple pyroptosis pathways: it promotes caspase-11-mediated non-canonical pyroptosis downstream of Bak/Bax, and activates AIM2/GSDMD pyroptosis in podocytes; separately, ATF4 was identified as a transcriptional driver of GBP2 that promotes STAT1–GBP2 interaction and NLRP3-dependent pyroptosis.","evidence":"Bak/Bax-KO MEFs with caspase-11 assays [PMID:41025249]; AIM2 rescue experiment in podocytes [PMID:41855126]; ATF4-KO mice and STAT1–GBP2 Co-IP [PMID:41563239]","pmids":["41025249","41855126","41563239"],"confidence":"Medium","gaps":["Whether GBP2 directly binds caspase-11 or acts through LPS aggregation in this context is unresolved","The direct molecular link between GBP2 and AIM2 activation has not been identified","Whether ATF4-driven GBP2 expression is relevant beyond drug-induced kidney injury is untested"]},{"year":null,"claim":"Major open questions remain: what structural features of GBP2 underlie its polymerization on LPS, how its GTPase cycle controls effector switching between different immune outputs (pyroptosis, ferroptosis, mitophagy inhibition), and whether the phase separation mechanism operates during infection as well as in tumor immunity.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of human GBP2 polymer or GBP2–LPS complex","GTPase-cycle-dependent regulation of effector choice is undefined","Integration of nuclear mRNA surveillance function (yeast) with innate immune roles (mammalian) across evolution is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,3,7,8]},{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[10,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,17,18]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[17]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,5,8]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,7,8,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11,13,17,25,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,17,24,27]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,16]}],"complexes":["TREX/THO complex (yeast, recruited to)"],"partners":["SHP1","STAT1","NIX","EIF4G1","MEX67","OTUD5","THO2"],"other_free_text":[]},"mechanistic_narrative":"GBP2 is a multifunctional interferon-γ-inducible large GTPase that operates in mRNA quality control (in yeast) and innate immune defense (in mammals). In Saccharomyces cerevisiae, Gbp2 is an SR-like shuttling RNA-binding protein cotranscriptionally loaded onto nascent mRNA via the TREX/THO complex through its RRM3 domain; it surveys splicing fidelity by recruiting TRAMP to defective transcripts for nuclear exosome degradation and loads the export receptor Mex67 onto correctly spliced mRNAs, while also functioning as a cytoplasmic translation repressor through RGG-motif-dependent binding of eIF4G1 [PMID:14769921, PMID:24452287, PMID:26602689, PMID:33910495]. In mammalian innate immunity, human GBP2 polymerizes and aggregates free LPS to enhance caspase-4 activation and non-canonical inflammasome-driven pyroptosis, and promotes AIM2/GSDMD-dependent pyroptosis in additional contexts [PMID:37023136, PMID:41855126, PMID:41025249]. GBP2 also undergoes IFN-γ-induced phase separation via an intrinsically disordered region to sequester the phosphatase SHP1, thereby sustaining STAT1 activation, suppressing SLC7A11, and sensitizing tumor cells to ferroptosis; separately, geranylgeranylation drives GBP2 mitochondrial translocation where it binds the mitophagy receptor NIX via its GTPase domain and promotes NIX proteasomal degradation, impairing mitophagy in dopaminergic neurons [PMID:41444224, PMID:41570768]."},"prefetch_data":{"uniprot":{"accession":"P32456","full_name":"Guanylate-binding protein 2","aliases":["GTP-binding protein 2","GBP-2","HuGBP-2","Guanine nucleotide-binding protein 2","Interferon-induced guanylate-binding protein 2"],"length_aa":591,"mass_kda":67.2,"function":"Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (PubMed:31091448). Hydrolyzes GTP to GMP in 2 consecutive cleavage reactions, but the major reaction product is GDP (PubMed:8706832). Following infection, recruited to the pathogen-containing vacuoles or vacuole-escaped bacteria and acts as a positive regulator of inflammasome assembly by promoting the release of inflammasome ligands from bacteria (By similarity). Acts by promoting lysis of pathogen-containing vacuoles, releasing pathogens into the cytosol (By similarity). Following pathogen release in the cytosol, promotes recruitment of proteins that mediate bacterial cytolysis: this liberates ligands that are detected by inflammasomes, such as lipopolysaccharide (LPS) that activates the non-canonical CASP4/CASP11 inflammasome or double-stranded DNA (dsDNA) that activates the AIM2 inflammasome (By similarity). Confers protection to the protozoan pathogen Toxoplasma gondii (By similarity). 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 many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GBP2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P32456","domains":[{"cath_id":"3.40.50.300","chopping":"38-152_167-278","consensus_level":"high","plddt":89.4604,"start":38,"end":278},{"cath_id":"1.20.1000.10","chopping":"326-534","consensus_level":"high","plddt":91.9054,"start":326,"end":534}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P32456","model_url":"https://alphafold.ebi.ac.uk/files/AF-P32456-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P32456-F1-predicted_aligned_error_v6.png","plddt_mean":89.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GBP2","jax_strain_url":"https://www.jax.org/strain/search?query=GBP2"},"sequence":{"accession":"P32456","fasta_url":"https://rest.uniprot.org/uniprotkb/P32456.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P32456/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P32456"}},"corpus_meta":[{"pmid":"14769921","id":"PMC_14769921","title":"Cotranscriptional 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immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and RNA-IP with multiple orthogonal methods, highly cited foundational paper\",\n      \"pmids\": [\"14769921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Gbp2 is a shuttling poly(A)+ RNA-binding protein whose nuclear import depends on the receptor Mtr10 and the SR kinase Sky1; deletion of MTR10 shifts Gbp2 to the cytoplasm and increases its poly(A)+ RNA binding, indicating Mtr10 mediates dissociation of Gbp2 from mRNA in the cytoplasm; nuclear export of Gbp2 is coupled to mRNA export and requires RNA Pol II transcription.\",\n      \"method\": \"Genetic deletion, subcellular fractionation/localization, RNA-binding assay, overexpression toxicity assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and biochemical approaches establishing import receptor, kinase dependency, and functional consequence\",\n      \"pmids\": [\"12634846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"For IFN-γ-induced transcription of the gbp2 gene, STAT1 binds the promoter independently of IRF1 and recruits CBP/HDAC1 and drives histone H4 hyperacetylation; STAT1 S727 phosphorylation (in its transactivation domain) is required for CBP recruitment and RNA Pol II association; IRF1 binds subsequently and directly contacts RNA Pol II-containing complexes, being required for productive transcription initiation.\",\n      \"method\": \"ChIP in WT/stat1−/−/irf1−/− cells, STAT1-S727A mutant analysis, co-immunoprecipitation 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 — multiple genetic backgrounds, mutagenesis, and ChIP with functional readout; highly cited\",\n      \"pmids\": [\"17293456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Gbp2 and Hrb1 act as mRNA surveillance/quality-control factors: they bind pre-mRNAs and the spliceosome during splicing, are required for stable binding of the TRAMP complex to spliceosome-associated transcripts (targeting faulty RNAs to the nuclear exosome), and upon completion of correct splicing recruit the export receptor Mex67 to allow nuclear export; their absence causes leakage of unspliced pre-mRNAs into the cytoplasm.\",\n      \"method\": \"RNA immunoprecipitation, genetic deletion with quantitative pre-mRNA export assay, co-immunoprecipitation with spliceosome/TRAMP components\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, clean KO phenotype with specific molecular mechanism defined\",\n      \"pmids\": [\"24452287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IRGM proteins (Irgm1, Irgm3) indirectly regulate the intracellular localization of murine Gbp2 through modulation of autophagic flux; in the absence of Irgm1/Irgm3 or Atg5, Gbp2 accumulates in LC3+ and p62/Sqstm1+ autophagic compartments; Irgm3 does not directly co-immunoprecipitate with Gbp2 (unlike its interaction with Irgb6), indicating an indirect mechanism via autophagy regulation.\",\n      \"method\": \"Immunofluorescence co-localization, co-immunoprecipitation, Atg5-KO cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional context, but mechanism is indirect and inferred from autophagy perturbation\",\n      \"pmids\": [\"21757726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Murine GBP-2 is prenylated via its 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\": \"Radiolabeled mevalonate incorporation assay, subcellular fractionation\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical prenylation assay with localization data, single study\",\n      \"pmids\": [\"9858320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the yeast THO•Sub2 complex at 3.7 Å resolution reveals THO stabilizes a semi-open conformation of the Sub2 ATPase via Tho2 interactions; THO interacts with the SR-like protein Gbp2 through both its RS domain and RRM domains, with cross-linking mass spectrometry showing RRM domains of Gbp2 are proximal to the Tho2 C-terminal domain, suggesting THO serves as a landing pad to configure Gbp2 for mRNP loading.\",\n      \"method\": \"Cryo-EM structure determination, cross-linking mass spectrometry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with cross-linking MS validation\",\n      \"pmids\": [\"33787496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NMR structures of Gbp2 RRM1 and RRM2 show they preferentially bind RNAs containing the core motif GGUG, 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 its N-terminal extension blocking the canonical binding interface, but instead mediates interaction with the THO/TREX complex; key residues in RRM3 essential for THO interaction were identified and genetic interaction with Tho2 was confirmed.\",\n      \"method\": \"NMR structure determination, RNA binding assays, mutagenesis, yeast genetic epistasis (double deletion synthetic phenotype)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structures with mutagenesis and genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"26602689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Gbp2 localizes to cytoplasmic stress granules upon heat shock and oxidative stress, directly binds translation initiation factor eIF4G1 via its RGG motif (mapped to a region overlapping with another repressor Sbp1), and acts as a translation repressor: tethering Gbp2 to a reporter mRNA reduces its translation in vivo, and Gbp2 directly represses translation in vitro in an RGG-motif-dependent manner.\",\n      \"method\": \"Fluorescence imaging, pulldown assay, polysome fractionation, in vivo tethering assay, in vitro translation assay, RGG-motif deletion mutant\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution of translation repression plus multiple in vivo assays with mutagenesis\",\n      \"pmids\": [\"33910495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Gbp2 (and Hrb1) continue quality control on exported transcripts in the cytoplasm: they support nonsense-mediated decay (NMD) by inhibiting translation and recruiting cytoplasmic degradation factors, thereby linking nuclear and cytoplasmic mRNA quality control.\",\n      \"method\": \"Genetic deletion with NMD reporter assays, functional epistasis analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — review/synthesis paper consolidating experimental results, functional assays described\",\n      \"pmids\": [\"34681934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human GBP2, like GBP1, directly binds and aggregates 'free' LPS through protein polymerization; supplementation of recombinant polymerized GBP2 to an in vitro reaction is sufficient to enhance LPS-induced caspase-4 activation; GBP2 overexpression can restore gram-negative-induced pyroptosis in GBP1-knockout cells without binding to the bacterial surface, establishing that LPS aggregation (not bacterial surface binding) is sufficient for non-canonical inflammasome activation.\",\n      \"method\": \"In vitro caspase-4 activation assay with recombinant protein, GBP1-KO cell complementation, LPS aggregation assay, protein polymerization assay\",\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 with recombinant proteins plus cell-based genetic complementation\",\n      \"pmids\": [\"37023136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Toxoplasma gondii rhoptry pseudokinase ROP54 modulates host GBP2 loading onto the parasitophorous vacuole membrane; parasites lacking ROP54 show substantially increased GBP2 (but not IRGb6) loading onto the vacuole, indicating ROP54 specifically counteracts GBP2-mediated innate immune defense.\",\n      \"method\": \"Genetic deletion of ROP54 in T. gondii type II strain, immunofluorescence quantification of GBP2 loading, in vivo virulence assay, macrophage clearance assay\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic deletion with specific phenotypic readout of GBP2 loading\",\n      \"pmids\": [\"27303719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In glioblastoma cells, GBP2 promotes cell migration and invasion via a GBP2/Stat3/fibronectin (FN1) signaling cascade: GBP2 overexpression induces FN1 at mRNA and protein levels, Stat3 pathway inhibition prevents GBP2-promoted FN1 induction and invasion, and GBP2 promotes tumor growth and invasion in mouse xenograft models.\",\n      \"method\": \"RNAi knockdown and overexpression, in vitro migration/invasion assays, Stat3 inhibitor, in vivo mouse tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD/OE with pharmacological pathway inhibition and in vivo validation, single lab\",\n      \"pmids\": [\"32518375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human GBP2 promotes STAT1 phosphorylation by competing with SHP1 for binding to STAT1 in microsatellite-stable colorectal cancer cells, enhancing antigen processing/presentation and CXCL10/11 expression upon IFN-γ stimulation.\",\n      \"method\": \"Co-immunoprecipitation (GBP2/SHP1/STAT1), GBP2 knockout, western blot for p-STAT1, cytokine measurement\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP establishing competitive binding plus KO functional phenotype, single lab\",\n      \"pmids\": [\"35383115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP-2 (murine) inhibits migration and invadosome formation in breast cancer cells downstream of Rho GTPase regulation, without affecting proliferation; GBP-2 expression is inversely correlated with aggressiveness/metastasis in 4T1 vs. 67NR murine breast cancer cell lines.\",\n      \"method\": \"GBP-2 expression alteration, migration assays, invadosome formation assay, Rho GTPase activity measurement\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD/OE with specific cellular phenotype and pathway placement via Rho GTPase measurement\",\n      \"pmids\": [\"34830789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Murine Gbp1 and Gbp2 are ubiquitinated independently of Toxoplasma gondii infection, as identified by mass spectrometry detection of di-glycine ubiquitin remnants on both proteins in IFNγ-stimulated MEFs.\",\n      \"method\": \"Mass spectrometry-based ubiquitinomics (di-glycine remnant profiling) in MEFs\",\n      \"journal\": \"BMC research notes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct MS identification of ubiquitination sites, but writer/eraser not identified\",\n      \"pmids\": [\"29510761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Parkinson's disease models, GBP2 undergoes geranylgeranylation (a prenylation modification) driving its accumulation at mitochondria, where it directly binds the mitophagy receptor NIX via its large GTPase domain and promotes NIX ubiquitin-proteasomal degradation, thereby suppressing NIX-mediated mitophagy and causing dopaminergic neuron loss; pharmacological inhibition of geranylgeranylation with GGTI298 attenuates MPTP-induced neurotoxicity.\",\n      \"method\": \"Co-immunoprecipitation (GBP2–NIX), GBP2 knockdown in vivo and in vitro, mitophagy assays, proteasome inhibitor rescue, NIX KD epistasis, GGTI298 pharmacological inhibition, MPTP mouse model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding identified by Co-IP, domain mapping, epistasis with NIX KD, in vivo pharmacological validation\",\n      \"pmids\": [\"41570768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP2 undergoes phase separation through an intrinsically disordered region upon IFN-γ stimulation, forming condensates that sequester SHP1 and sustain STAT1 activation; this enhances STAT1-driven suppression of SLC7A11, sensitizing melanoma tumor cells to ferroptosis; disrupting GBP2 phase separation impairs ferroptosis and tumor control by T cells.\",\n      \"method\": \"Phase separation assay, intrinsically disordered region mutagenesis, co-immunoprecipitation (GBP2–SHP1), western blot for p-STAT1/SLC7A11, HMGB1 release measurement, in vivo tumor growth assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phase separation with mutagenesis, direct SHP1 sequestration by Co-IP, functional downstream pathway validation with in vivo confirmation\",\n      \"pmids\": [\"41444224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EV-packaged GBP2 from macrophages directly binds OTUD5 (a deubiquitinase) and promotes GPX4 ubiquitination and degradation in pulmonary vascular endothelial cells, thereby driving ferroptosis and vascular barrier disruption in sepsis-associated lung injury; the small molecule Plantainoside D inhibits GBP2–OTUD5 interaction and reduces GPX4 ubiquitination.\",\n      \"method\": \"RNA interference, Co-IP (GBP2–OTUD5), AAV transfection, endothelial-specific Gpx4-KO mice, cellular thermal shift assay, molecular docking/dynamics, ubiquitination assay\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding by Co-IP, ubiquitination assay with KO validation, multiple orthogonal in vivo and in vitro methods\",\n      \"pmids\": [\"40156957\"],\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, western blot for Notch1 pathway markers, cytokine measurement\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway activation assay without direct binding partner identification\",\n      \"pmids\": [\"37622120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GBP2 directly interacts with kinesin family member KIF22 in glioma cells and regulates EGFR signaling through the KIF22/EGFR axis to promote glioma cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation (GBP2–KIF22), GBP2 knockdown/overexpression, EGFR signaling western blot, in vitro proliferation/migration assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with KD/OE functional assay, single lab\",\n      \"pmids\": [\"35436989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GBP2 inhibits pathological retinal angiogenesis by suppressing VEGFA expression and secretion through inhibition of the AKT/mTOR signaling pathway in retinal pigment epithelial cells and OIR mouse retinas.\",\n      \"method\": \"GBP2 silencing/overexpression, western blot for AKT/mTOR/VEGFA, VEGFA ELISA, conditioned medium angiogenesis assay with HUVECs, OIR mouse model\",\n      \"journal\": \"Microvascular research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KD/OE with pathway inhibition readout, no direct binding partner identified, single lab\",\n      \"pmids\": [\"38636926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In silicosis, GBP2 in macrophages activates the c-Jun pathway to promote M2 macrophage polarization and inflammatory factor secretion; in epithelial cells, GBP2 promotes epithelial-mesenchymal transition (EMT) by upregulating the transcription factor KLF8.\",\n      \"method\": \"Western blot, RT-qPCR, GBP2 knockdown/overexpression, immunofluorescence in THP-1 cells and epithelial cells\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KD/OE with pathway markers, no direct binding demonstrated, single lab\",\n      \"pmids\": [\"40620118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ATF4 (master regulator of integrated stress response) promotes GBP2 expression and phosphorylated STAT1 interaction with GBP2, leading to NLRP3 inflammasome activation and tubular epithelial cell pyroptosis in drug-induced AKI; ATF4 suppression disrupts STAT1–GBP2 interaction and attenuates pyroptosis.\",\n      \"method\": \"Single-cell RNA-seq, co-immunoprecipitation (STAT1–GBP2), luciferase reporter, ATF4-specific KO mice, western blotting, pharmacological ATF4 inhibition\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of STAT1–GBP2 complex with genetic KO and pharmacological validation, multiple methods\",\n      \"pmids\": [\"41563239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP2 promotes podocyte pyroptosis in lupus nephritis via the AIM2 pathway: Gbp2 knockdown reduces GSDMD and AIM2 expression and decreases IL-1β/IL-18 secretion, while Gbp2 overexpression exacerbates these effects; the pyroptosis suppression from Gbp2 knockdown is partially restored by concurrent AIM2 overexpression.\",\n      \"method\": \"siRNA knockdown, overexpression, rescue experiment (AIM2 OE), western blot, cytokine ELISA, in vitro LPS/ATP podocyte pyroptosis model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic epistasis (rescue experiment) placing GBP2 upstream of AIM2 in pyroptosis pathway\",\n      \"pmids\": [\"41855126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP2 suppresses MLV replication by inhibiting furin protease cleavage of the viral envelope glycoprotein SU-TM junction; the sensitivity of MLV Env to GBP2 and furin is determined by the amino acid sequence at the SU-TM cleavage site; substitution of the ecotropic cleavage site sequence with XMRV sequence confers resistance to GBP2, and vice versa.\",\n      \"method\": \"Furin silencing, cleavage site amino acid substitution mutagenesis, infection efficiency assay, western blot for Env cleavage\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — site-directed mutagenesis of substrate cleavage site defining GBP2 mechanism of viral restriction\",\n      \"pmids\": [\"39337476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In macrophages, GBP2 promotes M1 polarization and NF-κB pathway activation by recruiting Pin1; nanovaccine-enhanced Gbp2 expression drives TAM reprogramming to M1 phenotype through the Gbp2-Pin1-NFκB pathway.\",\n      \"method\": \"RNA-seq, scRNA-seq, mass spectrometry proteomics, GBP2 targeting in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Pin1 interaction identified by proteomics without direct binding validation, pathway inferred from omics\",\n      \"pmids\": [\"39985265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP2 promotes non-canonical pyroptosis through the GBP2-caspase-11 axis during Vibrio vulnificus and Salmonella infections; pro-apoptotic proteins Bak and Bax act as positive regulators upstream of Gbp2 upregulation and caspase-11 activation, while anti-apoptotic MCL-1 does not affect this process.\",\n      \"method\": \"Bak-KO and Bax-KO MEFs, caspase-11 activation assay, LDH release, GBP2 western blot\",\n      \"journal\": \"Journal of microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using KO cells placing Bak/Bax upstream of Gbp2 in pyroptosis pathway\",\n      \"pmids\": [\"41025249\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GBP2 is an IFN-γ-inducible large GTPase with multiple mechanistic roles: in yeast, it is an SR-like shuttling protein recruited cotranscriptionally via the TREX/THO complex (whose interaction is mediated by its RRM3 domain) to perform nuclear mRNA quality control by surveilling splicing, recruiting TRAMP to defective transcripts, and loading Mex67 onto mature mRNAs for export, while also acting as a cytoplasmic translation repressor via RGG-motif-dependent eIF4G1 binding; in mammalian innate immunity, human GBP2 directly polymerizes free LPS and aggregates it to enhance caspase-4 activation, facilitates pyroptosis (including via the non-canonical caspase-11 axis and the AIM2/GSDMD axis), undergoes IFN-γ-induced phase separation through an intrinsically disordered region to sequester SHP1 and sustain STAT1 activation (thereby suppressing SLC7A11 and promoting ferroptosis), and upon geranylgeranylation-driven mitochondrial translocation directly binds the mitophagy receptor NIX via its GTPase domain to promote NIX degradation and impair mitophagy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GBP2 is a multifunctional interferon-γ-inducible large GTPase that operates in mRNA quality control (in yeast) and innate immune defense (in mammals). In Saccharomyces cerevisiae, Gbp2 is an SR-like shuttling RNA-binding protein cotranscriptionally loaded onto nascent mRNA via the TREX/THO complex through its RRM3 domain; it surveys splicing fidelity by recruiting TRAMP to defective transcripts for nuclear exosome degradation and loads the export receptor Mex67 onto correctly spliced mRNAs, while also functioning as a cytoplasmic translation repressor through RGG-motif-dependent binding of eIF4G1 [PMID:14769921, PMID:24452287, PMID:26602689, PMID:33910495]. In mammalian innate immunity, human GBP2 polymerizes and aggregates free LPS to enhance caspase-4 activation and non-canonical inflammasome-driven pyroptosis, and promotes AIM2/GSDMD-dependent pyroptosis in additional contexts [PMID:37023136, PMID:41855126, PMID:41025249]. GBP2 also undergoes IFN-γ-induced phase separation via an intrinsically disordered region to sequester the phosphatase SHP1, thereby sustaining STAT1 activation, suppressing SLC7A11, and sensitizing tumor cells to ferroptosis; separately, geranylgeranylation drives GBP2 mitochondrial translocation where it binds the mitophagy receptor NIX via its GTPase domain and promotes NIX proteasomal degradation, impairing mitophagy in dopaminergic neurons [PMID:41444224, PMID:41570768].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the post-translational modification status of GBP2: murine GBP-2 was shown to be geranylgeranylated at its C-terminal CaaX motif yet remain primarily cytosolic, raising the question of what triggers its membrane relocalization.\",\n      \"evidence\": \"Radiolabeled mevalonate incorporation in COS cells with subcellular fractionation\",\n      \"pmids\": [\"9858320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stimulus or signal triggering membrane translocation was unknown\", \"Whether prenylation is required for function was untested\", \"Human GBP2 prenylation status not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining yeast Gbp2 as a shuttling mRNA-binding protein whose nuclear-cytoplasmic transport depends on the import receptor Mtr10 and the SR kinase Sky1, establishing its identity as an SR-like protein coupled to mRNA export.\",\n      \"evidence\": \"Genetic deletion of MTR10, subcellular localization, poly(A)+ RNA binding assays in S. cerevisiae\",\n      \"pmids\": [\"12634846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Gbp2 is loaded onto mRNA in the nucleus was unknown\", \"Functional consequence of Gbp2 shuttling for mRNA fate was not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolving how Gbp2 is recruited to mRNA: cotranscriptional loading via the TREX complex and association with the CTD kinase Ctk1 showed that Gbp2 joins nascent transcripts during elongation, not post-transcriptionally.\",\n      \"evidence\": \"Co-IP, RNA-IP, and ChIP on actively transcribed genes in S. cerevisiae\",\n      \"pmids\": [\"14769921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which domain of Gbp2 mediates TREX interaction was unresolved\", \"Functional purpose of cotranscriptional loading (surveillance vs. export) was unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining the transcriptional regulation of the mammalian gbp2 gene: STAT1 S727 phosphorylation recruits CBP to the promoter, and IRF1 subsequently contacts RNA Pol II for productive transcription, establishing the two-step IFN-γ transcriptional activation mechanism.\",\n      \"evidence\": \"ChIP in WT, stat1−/−, and irf1−/− cells with STAT1-S727A mutagenesis\",\n      \"pmids\": [\"17293456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this promoter architecture is shared by other GBP family members was not tested\", \"Post-transcriptional regulation of GBP2 mRNA was not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing yeast Gbp2 as a nuclear mRNA quality-control factor: Gbp2 binds pre-mRNAs on the spliceosome, recruits TRAMP to target faulty transcripts for exosome degradation, and upon correct splicing loads the export receptor Mex67, gating mRNA export on splicing fidelity.\",\n      \"evidence\": \"RNA-IP, co-IP with spliceosome/TRAMP components, quantitative pre-mRNA export assays in deletion strains\",\n      \"pmids\": [\"24452287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Gbp2 distinguishes correctly from incorrectly spliced transcripts at the molecular level was unclear\", \"Whether Gbp2 surveils all intron-containing genes equally was not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Structural basis of Gbp2 RNA recognition and TREX interaction: NMR structures revealed RRM1/2 bind GGUG-containing RNA while RRM3 does not bind RNA but instead mediates interaction with THO/TREX, resolving the domain-level division of labor.\",\n      \"evidence\": \"NMR structure determination, RNA binding assays, mutagenesis, genetic epistasis with Tho2 in S. cerevisiae\",\n      \"pmids\": [\"26602689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic-resolution structure of the Gbp2–THO complex was lacking\", \"How RRM3–THO interaction is released after mRNP remodeling was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that mammalian GBP2 is recruited to pathogen-containing vacuoles and is actively counteracted by pathogen effectors: T. gondii ROP54 specifically limits GBP2 loading onto the parasitophorous vacuole.\",\n      \"evidence\": \"ROP54-KO T. gondii, quantitative immunofluorescence of GBP2 loading on vacuoles in macrophages\",\n      \"pmids\": [\"27303719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target of ROP54 on GBP2 was not identified\", \"Whether GBP2 vacuolar recruitment requires GTPase activity was untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM of the THO•Sub2 complex confirmed that THO serves as a structural landing pad for Gbp2 loading, with cross-linking MS placing Gbp2 RRM domains near the Tho2 C-terminal domain, providing the first structural view of this interaction.\",\n      \"evidence\": \"Cryo-EM at 3.7 Å resolution with cross-linking mass spectrometry\",\n      \"pmids\": [\"33787496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"A co-structure of THO bound to full-length Gbp2 was not obtained\", \"Dynamics of Gbp2 handoff from THO to mRNA were not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanding Gbp2 beyond nuclear surveillance to cytoplasmic translation repression: Gbp2 localizes to stress granules, directly binds eIF4G1 via its RGG motif, and represses translation both in vivo and in vitro, linking its nuclear and cytoplasmic mRNA regulatory roles.\",\n      \"evidence\": \"In vitro translation repression assay, tethering assay, RGG-motif deletion, pulldown with eIF4G1 in S. cerevisiae\",\n      \"pmids\": [\"33910495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether translation repression and stress granule localization are functionally separable was unclear\", \"Physiological conditions activating cytoplasmic Gbp2 repression beyond heat shock were not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing the mammalian GBP2–SHP1–STAT1 axis: GBP2 competes with phosphatase SHP1 for STAT1 binding, sustaining STAT1 phosphorylation and IFN-γ signaling in colorectal cancer cells.\",\n      \"evidence\": \"Co-IP of GBP2/SHP1/STAT1, GBP2 knockout, p-STAT1 western blot in microsatellite-stable CRC cells\",\n      \"pmids\": [\"35383115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between GBP2 and STAT1 was not mapped\", \"Whether GBP2 GTPase activity is required for SHP1 displacement was untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that human GBP2 directly polymerizes and aggregates free LPS to enhance caspase-4 activation, establishing a GBP1-independent mechanism for non-canonical inflammasome engagement that does not require bacterial surface binding.\",\n      \"evidence\": \"In vitro caspase-4 activation with recombinant GBP2, LPS aggregation assay, GBP1-KO cell complementation\",\n      \"pmids\": [\"37023136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GBP2 polymerization on LPS was not resolved\", \"Relative contributions of GBP2 vs. GBP1 to LPS sensing in physiological infection were not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple parallel advances defined new GBP2 effector mechanisms: (1) IFN-γ-induced phase separation via an intrinsically disordered region sequesters SHP1 to sustain STAT1 and drive ferroptosis; (2) geranylgeranylation drives mitochondrial translocation where GBP2 binds NIX and promotes its proteasomal degradation, impairing mitophagy in dopaminergic neurons; (3) GBP2 in macrophage-derived EVs binds OTUD5 to promote GPX4 ubiquitination and ferroptosis in endothelial cells; (4) GBP2 restricts MLV by inhibiting furin-mediated Env cleavage at the SU-TM junction.\",\n      \"evidence\": \"Phase separation/IDR mutagenesis with in vivo tumor models [PMID:41444224]; Co-IP of GBP2–NIX with GTPase domain mapping and MPTP mouse model [PMID:41570768]; Co-IP of GBP2–OTUD5 with GPX4 ubiquitination assay and endothelial-specific Gpx4-KO mice [PMID:40156957]; furin silencing and cleavage-site mutagenesis of MLV Env [PMID:39337476]\",\n      \"pmids\": [\"41444224\", \"41570768\", \"40156957\", \"39337476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phase separation and LPS polymerization activities are coordinated in infection is unknown\", \"The GBP2–OTUD5 interaction domain has not been mapped\", \"Whether NIX binding requires GTP hydrolysis or only GTP binding is unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"GBP2 was placed upstream of multiple pyroptosis pathways: it promotes caspase-11-mediated non-canonical pyroptosis downstream of Bak/Bax, and activates AIM2/GSDMD pyroptosis in podocytes; separately, ATF4 was identified as a transcriptional driver of GBP2 that promotes STAT1–GBP2 interaction and NLRP3-dependent pyroptosis.\",\n      \"evidence\": \"Bak/Bax-KO MEFs with caspase-11 assays [PMID:41025249]; AIM2 rescue experiment in podocytes [PMID:41855126]; ATF4-KO mice and STAT1–GBP2 Co-IP [PMID:41563239]\",\n      \"pmids\": [\"41025249\", \"41855126\", \"41563239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GBP2 directly binds caspase-11 or acts through LPS aggregation in this context is unresolved\", \"The direct molecular link between GBP2 and AIM2 activation has not been identified\", \"Whether ATF4-driven GBP2 expression is relevant beyond drug-induced kidney injury is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions remain: what structural features of GBP2 underlie its polymerization on LPS, how its GTPase cycle controls effector switching between different immune outputs (pyroptosis, ferroptosis, mitophagy inhibition), and whether the phase separation mechanism operates during infection as well as in tumor immunity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of human GBP2 polymer or GBP2–LPS complex\", \"GTPase-cycle-dependent regulation of effector choice is undefined\", \"Integration of nuclear mRNA surveillance function (yeast) with innate immune roles (mammalian) across evolution is unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 3, 7, 8]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [10, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 17, 18]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11, 13, 17, 25, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 17, 24, 27]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 16]}\n    ],\n    \"complexes\": [\n      \"TREX/THO complex (yeast, recruited to)\"\n    ],\n    \"partners\": [\n      \"SHP1\",\n      \"STAT1\",\n      \"NIX\",\n      \"eIF4G1\",\n      \"Mex67\",\n      \"OTUD5\",\n      \"Tho2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}