{"gene":"GBP5","run_date":"2026-04-28T18:06:52","timeline":{"discoveries":[{"year":2012,"finding":"GBP5 promotes selective NLRP3 inflammasome assembly and activation in response to pathogenic bacteria and soluble (but not crystalline) inflammasome priming agents. Gbp5-/- mice show pronounced caspase-1 and IL-1β/IL-18 cleavage defects in vitro and impaired Nlrp3-dependent inflammatory responses in vivo, establishing GBP5 as a non-NLR/ALR rheostat for NLRP3 inflammasome activation.","method":"Gbp5 knockout mouse generation, in vitro macrophage caspase-1/IL-1β/IL-18 cleavage assays, in vivo infection models, genetic epistasis with Nlrp3","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — knockout mouse with multiple orthogonal readouts, epistasis with NLRP3, replicated across in vitro and in vivo settings; foundational paper with >400 citations","pmids":["22461501"],"is_preprint":false},{"year":2017,"finding":"GBP5 inhibits influenza A virus replication by interacting with the NF-κB essential modulator (NEMO) complex and stimulating NF-κB signaling, thereby enhancing interferon and proinflammatory cytokine expression.","method":"Overexpression and knockdown in A549 cells, co-immunoprecipitation with NEMO, viral replication assays, cytokine measurement","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 2–3 — single lab, Co-IP with NEMO plus functional KD/OE assays with defined antiviral phenotype","pmids":["28376501"],"is_preprint":false},{"year":2020,"finding":"GBP5 inhibits RSV replication by promoting secretion of the RSV small hydrophobic (SH) viroporin protein via microvesicles, reducing its intracellular levels. Golgi localization (dependent on the C-terminal isoprenylation motif, C583) but not GTPase activity is required for this antiviral function. RSV G protein counteracts GBP5 by upregulating the E3 ubiquitin ligase DZIP3, which degrades GBP5 via K48-linked ubiquitination and the proteasome.","method":"C-terminal mutants (GBP5-C583A, GBP5-ΔC) and GTPase-dead mutants, subcellular localization imaging, RSV replication assays, DZIP3 overexpression and siRNA knockdown, proteasome inhibitor experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 — structure-function mutagenesis, localization studies with functional consequence, defined E3 ligase mechanism, multiple orthogonal methods in single study","pmids":["32796072"],"is_preprint":false},{"year":2021,"finding":"GBP5 promotes GBM cell proliferation, migration, and invasion through the Src/ERK1/2/MMP3 signaling axis. Silencing GBP5 by RNA interference impairs tumor growth and prolongs survival in mouse GBM models.","method":"RNA interference knockdown, overexpression, in vitro proliferation/migration/invasion assays, in vivo mouse tumor model, western blotting for Src/ERK1/2/MMP3 pathway","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO/KD with defined cellular and in vivo phenotypes and pathway identification, single lab","pmids":["33608513"],"is_preprint":false},{"year":2021,"finding":"GBP5 knockdown in TNBC cells suppresses cellular migration, IFN-γ/STAT1 and TNF-α/NF-κB signaling, and PD-L1 expression, indicating GBP5 regulates metastatic potential and immune checkpoint ligand expression via these signaling axes.","method":"siRNA knockdown in TNBC cell lines, Transwell migration assay, western blotting for STAT1/NF-κB pathways and PD-L1, GSEA computational analysis","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2–3 — KD with multiple pathway readouts, single lab with functional and signaling data","pmids":["33916322"],"is_preprint":false},{"year":2021,"finding":"GBP5 induces hepatocyte apoptosis through activation of both the calpain/caspase-12/caspase-3 (intrinsic) and TNFα/caspase-8/caspase-3 (extrinsic) pathways. Liver-specific overexpression of GBP5 is sufficient to induce liver injury, while Gbp5 knockout ameliorates GalN/LPS-induced liver injury.","method":"Gbp5 knockout mice, liver-specific adenoviral overexpression, GalN/LPS injury model, calpain inhibitor and caspase-3 inhibitor rescue experiments, western blotting","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 — gain- and loss-of-function in vivo with pharmacological rescue of specific apoptotic pathway nodes, multiple orthogonal mechanistic approaches","pmids":["34958688"],"is_preprint":false},{"year":2021,"finding":"GBP5 transcription is directly activated by the transcription factor BATF, which binds the GBP5 promoter, thereby promoting NLRP3 inflammasome activation and IL-1β/IL-18 production in sepsis-associated liver injury.","method":"Chromatin immunoprecipitation (ChIP), promoter reporter assays, GBP5 overexpression in LPS-induced SALI model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay establish direct transcriptional regulation; single lab","pmids":["34042221"],"is_preprint":false},{"year":2022,"finding":"GBP5 knockdown suppresses M1 macrophage polarization in part by repressing NF-κB signaling pathway activation, reducing expression of IL-6, iNOS, and TNF-α.","method":"GBP5 siRNA in THP-1 cells and intradermal injection in mouse rosacea model, M1 marker gene expression analysis, NF-κB pathway western blotting","journal":"Journal of the European Academy of Dermatology and Venereology","confidence":"Medium","confidence_rationale":"Tier 2–3 — siRNA KD with defined macrophage polarization phenotype and NF-κB pathway readout, in vitro and in vivo","pmids":["36367676"],"is_preprint":false},{"year":2023,"finding":"IRF1 binds directly to the GBP5 promoter to enhance its transcription, and GBP5 in turn activates the NLRP3 inflammasome pathway to promote chondrocyte pyroptosis in osteoarthritis. Co-transfection with ad-IRF1 and siGBP5 demonstrates epistatic relationship.","method":"Dual luciferase reporter gene assay, chromatin immunoprecipitation (ChIP), siRNA and overexpression plasmid transfection, flow cytometry for pyroptosis, ELISA for IL-1β/IL-18","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay confirm direct IRF1-GBP5 promoter interaction; epistasis by co-transfection; single lab","pmids":["38229660"],"is_preprint":false},{"year":2023,"finding":"GBP5 is regulated by the IFNγ-JAK1-STAT1 axis and in turn induces CXCL8 expression; CXCL8 then feeds back to activate JAK1-STAT1 signaling, forming a positive feedback loop in gastric cancer cells.","method":"RNA-sequencing, western blotting, qPCR in gastric cancer cell lines, pathway inhibition experiments","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — RNA-seq plus functional validation of feedback loop, single lab","pmids":["37168340"],"is_preprint":false},{"year":2023,"finding":"Sinomenine directly binds GBP5 (KD = 3.486 µM as measured by binding affinity assay) and suppresses GBP5/P2X7R-NLRP3 pathway activity, reducing IL-1β and IL-18 production in macrophages and CIA mice.","method":"Solvent-induced protein precipitation (SIP) assay, molecular docking simulation, proteomics, binding affinity assay (KD determination), siRNA knockdown, western blotting","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 1–2 — direct binding measured by affinity assay with multiple orthogonal methods; single lab","pmids":["37482570"],"is_preprint":false},{"year":2024,"finding":"GBP5 is transcriptionally regulated by HDAC3 in macrophages; HDAC3 overexpression upregulates GBP5 reporter activity, while HDAC3 conditional knockout reduces IFN-γ-induced GBP5 transcription, and this reduction is linked to decreased NLRP3 inflammasome activation.","method":"Conditional knockout of Hdac3 in CX3CR1+ cells, RNA sequencing, GBP5 reporter assay with HDAC3 overexpression, RNA-seq validation, RGFP966 inhibitor treatment","journal":"International journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assay and conditional KO with RNA-seq mechanistic data; single lab","pmids":["38903915"],"is_preprint":false},{"year":2024,"finding":"GBP5 induces canonical pyroptosis in ovarian cancer cells through the JAK2/STAT1 pathway, and high GBP5-expressing cancer cells upregulate CXCL9/10/11, remodeling the tumor immune microenvironment toward increased M1 macrophage infiltration.","method":"GBP5 overexpression/knockdown in ovarian cancer cells and patient-derived organoids, invasion/migration assays, JAK2/STAT1 pathway western blotting, co-culture immune assays, immunohistochemistry","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway western blotting with gain/loss of function and organoid model; single lab","pmids":["38817865"],"is_preprint":false},{"year":2025,"finding":"GBP5 binds to STAT1 and facilitates its nuclear translocation, thereby enhancing STAT1 transcriptional activity and expression of downstream cytokines that drive innate lymphoid cell expansion in colitis. GBP5 does not directly drive gene transcription but acts as a co-facilitator of STAT1 activity.","method":"Co-immunoprecipitation (GBP5-STAT1 interaction), nuclear fractionation, Gbp5 knockout mouse colitis model, GBP5-deficient THP-1 transcriptomics, STAT1 overexpression rescue experiment","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP plus nuclear fractionation establishing mechanism, KO mouse with defined ILC phenotype, rescue by STAT1 overexpression; multiple orthogonal methods","pmids":["40055493"],"is_preprint":false},{"year":2025,"finding":"KRT9 is required for GBP5-mediated RSV-SH protein transport and antiviral activity. GBP5 acts as a bridge between KRT9 and RSV-SH protein; KRT9 directly interacts with GBP5 (but not RSV-SH), and a GBP5-binding domain was mapped on KRT9. Silencing KRT9 abrogates GBP5 and IFN-γ antiviral effects.","method":"Affinity mass spectrometry, co-immunoprecipitation, siRNA knockdown of KRT9, RSV replication assays, domain mapping experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — affinity MS plus Co-IP and KD with functional antiviral readout; single lab building on prior mechanistic study","pmids":["39835811"],"is_preprint":false},{"year":2025,"finding":"ERRγ binds to the GBP5 promoter to inhibit GBP5 transcription, thereby suppressing NLRP3 inflammasome assembly and pyroptosis in cardiomyocytes after myocardial infarction. Overexpression of GBP5 reverses the protective effects of ERRγ overexpression.","method":"Cardiomyocyte-specific ERRγ overexpression in vivo, GBP5 promoter binding assay, GBP5 overexpression epistasis experiment, NLRP3 inflammasome assembly assays, cardiac function measurements","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — promoter binding plus epistasis (GBP5 overexpression reverses ERRγ protection) in vivo; single lab","pmids":["40636987"],"is_preprint":false},{"year":2002,"finding":"Murine GBP5 encodes a 590 amino acid protein with GTP-binding motifs conserved with human GBP-1 and a C-terminal isoprenylation sequence. An alternatively spliced form lacking the second GTP-binding motif and the isoprenylation site was identified, indicating structural and functional diversity.","method":"cDNA cloning, sequence analysis, RNase protection assay, genomic mapping","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 3 — molecular cloning with domain identification; foundational structural characterization","pmids":["12396730"],"is_preprint":false},{"year":2004,"finding":"Human GBP5 is expressed as at least three splice variants (GBP-5a, -5b, -5ta) producing two proteins; GBP-5ta lacks the C-terminal 97 aa including the isoprenylation site. Protein expression in normal tissue is restricted to peripheral blood monocytes, while both isoforms are expressed in CTCL and melanoma cell lines.","method":"RT-PCR, western blotting with isoform-specific antibodies, SEREX immunogenicity testing","journal":"Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 — protein-level isoform characterization with antibody validation; localization to monocytes established by western blot","pmids":["15175044"],"is_preprint":false}],"current_model":"GBP5 is an IFN-γ-inducible large GTPase that functions as a rheostat for NLRP3 inflammasome assembly by promoting selective responses to soluble (not crystalline) activators and pathogenic bacteria; it physically binds STAT1 and facilitates its nuclear translocation to amplify downstream cytokine expression, localizes to the Golgi via its C-terminal isoprenylation motif (required for antiviral activity against RSV by promoting SH viroporin secretion), activates both extrinsic and intrinsic apoptosis pathways in hepatocytes, and is transcriptionally regulated by BATF, IRF1, HDAC3, and ERRγ, while being targeted for K48-ubiquitin-mediated proteasomal degradation by the E3 ligase DZIP3 during RSV infection."},"narrative":{"teleology":[{"year":2002,"claim":"Cloning of murine GBP5 established it as a GTP-binding protein with a C-terminal isoprenylation motif and alternative splicing producing isoforms with distinct domain architectures, providing the first structural framework for functional studies.","evidence":"cDNA cloning, sequence analysis, and RNase protection assay in mouse","pmids":["12396730"],"confidence":"Medium","gaps":["No enzymatic or GTPase activity measured","Functional consequence of alternative splicing unknown","No human ortholog characterized at protein level yet"]},{"year":2004,"claim":"Identification of three human GBP5 splice variants and restriction of protein expression to peripheral blood monocytes in normal tissue established the cell-type specificity relevant to its later-discovered innate immune functions.","evidence":"RT-PCR, isoform-specific western blotting in normal and tumor cell lines","pmids":["15175044"],"confidence":"Medium","gaps":["Expression in other immune cell types not surveyed comprehensively","Functional differences between GBP-5a/5b/5ta isoforms not tested"]},{"year":2012,"claim":"The central question of whether GBP5 has a defined innate immune effector function was answered: GBP5 selectively promotes NLRP3 inflammasome assembly in response to bacteria and soluble agents but not crystalline activators, establishing it as the first non-NLR/non-ALR rheostat for inflammasome gating.","evidence":"Gbp5 knockout mice, macrophage caspase-1/IL-1β/IL-18 cleavage assays, in vivo infection models, genetic epistasis with Nlrp3","pmids":["22461501"],"confidence":"High","gaps":["Molecular mechanism by which GBP5 distinguishes soluble from crystalline activators unknown","Direct physical interaction with NLRP3 or ASC not demonstrated","Whether GTPase activity is required for inflammasome function untested"]},{"year":2017,"claim":"GBP5's antiviral repertoire was extended beyond inflammasome activation when it was shown to inhibit influenza A virus replication by interacting with NEMO and stimulating NF-κB signaling, revealing a second effector axis.","evidence":"Co-immunoprecipitation with NEMO, knockdown and overexpression in A549 cells, viral replication assays","pmids":["28376501"],"confidence":"Medium","gaps":["NEMO interaction not confirmed by reciprocal IP or endogenous pull-down","Whether GTPase or isoprenylation motif is needed for NF-κB activation unknown","Single cell line tested"]},{"year":2020,"claim":"The mechanism of GBP5 antiviral activity against RSV was resolved: GBP5 promotes secretion of the RSV SH viroporin via microvesicles, requiring Golgi localization through C583 isoprenylation but not GTPase activity, while RSV counteracts GBP5 through DZIP3-mediated K48-ubiquitination and proteasomal degradation.","evidence":"C-terminal and GTPase-dead mutants, subcellular imaging, RSV replication assays, DZIP3 overexpression/siRNA, proteasome inhibitor rescue","pmids":["32796072"],"confidence":"High","gaps":["Identity of cargo receptor or vesicle machinery linking GBP5 to microvesicle secretion unknown","Whether DZIP3-mediated degradation occurs during other viral infections not tested"]},{"year":2021,"claim":"Multiple studies established that GBP5 transcription is directly regulated by BATF (activating) at the promoter and that GBP5 can activate both intrinsic (calpain/caspase-12/caspase-3) and extrinsic (TNFα/caspase-8/caspase-3) apoptosis in hepatocytes, broadening its cell-death effector functions beyond pyroptosis.","evidence":"ChIP and promoter reporter assays for BATF–GBP5 promoter; Gbp5 KO mice and liver-specific adenoviral overexpression in GalN/LPS injury model with calpain and caspase-3 inhibitor rescue","pmids":["34042221","34958688"],"confidence":"High","gaps":["Whether apoptosis induction requires GTPase activity or isoprenylation unknown","Mechanism linking GBP5 to calpain activation not defined at molecular level"]},{"year":2021,"claim":"GBP5 was placed in oncogenic and immune-evasion signaling: it promotes GBM tumor growth via Src/ERK1/2/MMP3 and sustains PD-L1 expression in TNBC through IFNγ/STAT1 and TNFα/NF-κB axes, indicating context-dependent pro-tumorigenic roles.","evidence":"siRNA/overexpression in GBM and TNBC cell lines, in vivo mouse GBM tumor model, Transwell migration, western blotting for pathway components","pmids":["33608513","33916322"],"confidence":"Medium","gaps":["Direct substrates or binding partners mediating Src or ERK activation not identified","Whether inflammasome function contributes to tumor phenotypes untested","Single-lab studies for each tumor type"]},{"year":2023,"claim":"Two additional transcriptional inputs to GBP5 were defined—IRF1 directly activates the GBP5 promoter to drive NLRP3-mediated chondrocyte pyroptosis, and GBP5 participates in a positive feedback loop with CXCL8 through JAK1-STAT1 signaling—consolidating GBP5 as a convergence node for multiple inflammatory transcription factors.","evidence":"ChIP and dual-luciferase reporter for IRF1; RNA-seq and pathway inhibition for CXCL8 feedback loop in gastric cancer cells","pmids":["38229660","37168340"],"confidence":"Medium","gaps":["Whether IRF1, BATF, and HDAC3 act combinatorially on the GBP5 promoter unknown","CXCL8 feedback loop demonstrated only in gastric cancer cells"]},{"year":2024,"claim":"HDAC3 was identified as a positive transcriptional regulator of GBP5 in macrophages, linking epigenetic control to inflammasome output, while GBP5 was shown to induce canonical pyroptosis in ovarian cancer cells via JAK2/STAT1 with consequent CXCL9/10/11-driven M1 macrophage recruitment.","evidence":"Conditional Hdac3 KO in CX3CR1+ cells with RNA-seq and reporter assays; GBP5 OE/KD in ovarian cancer cells and patient-derived organoids with immune co-culture","pmids":["38903915","38817865"],"confidence":"Medium","gaps":["Whether HDAC3 acts directly on GBP5 promoter chromatin or indirectly through another factor not resolved","Relative contribution of pyroptosis vs. chemokine secretion to tumor immune remodeling unclear"]},{"year":2025,"claim":"The mechanism by which GBP5 amplifies cytokine signaling was resolved: GBP5 physically binds STAT1 and facilitates its nuclear translocation without acting as a transcription factor itself, functioning as a co-facilitator of STAT1 activity that drives innate lymphoid cell expansion in colitis.","evidence":"Reciprocal co-immunoprecipitation, nuclear fractionation, Gbp5 KO mouse colitis model, STAT1 overexpression rescue in GBP5-deficient THP-1 cells","pmids":["40055493"],"confidence":"High","gaps":["Domain on GBP5 mediating STAT1 binding not mapped","Whether GBP5 also facilitates nuclear translocation of other STATs unknown"]},{"year":2025,"claim":"KRT9 was identified as the obligate partner bridging GBP5 to RSV-SH protein for antiviral viroporin secretion, with a mapped GBP5-binding domain on KRT9, explaining the cargo-specificity of the GBP5 secretory antiviral pathway. ERRγ was identified as a transcriptional repressor of GBP5 that suppresses inflammasome-mediated cardiomyocyte pyroptosis after myocardial infarction.","evidence":"Affinity mass spectrometry and Co-IP for KRT9–GBP5 interaction, KRT9 siRNA abolishing antiviral effect; ERRγ promoter binding assay and in vivo epistasis in cardiomyocytes","pmids":["39835811","40636987"],"confidence":"Medium","gaps":["Whether KRT9–GBP5 interaction occurs in non-RSV antiviral contexts unknown","ERRγ-GBP5 axis demonstrated only in cardiomyocytes; generalizability untested"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis and direct binding interface for GBP5-NLRP3/ASC interaction, (2) whether GTPase activity is dispensable for all GBP5 functions or only for RSV-related secretion, (3) the integration of multiple transcriptional inputs (BATF, IRF1, HDAC3, ERRγ) at the GBP5 promoter, and (4) the molecular mechanism by which GBP5 distinguishes soluble from crystalline NLRP3 activators.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure or cryo-EM of GBP5 alone or in complex","No reconstituted in vitro inflammasome assembly with purified GBP5","Isoform-specific functions of GBP-5a/5b/5ta remain untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[16,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13,14]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,7,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,9,13]}],"complexes":["NLRP3 inflammasome"],"partners":["NLRP3","STAT1","NEMO","DZIP3","KRT9","BATF","IRF1","HDAC3"],"other_free_text":[]},"mechanistic_narrative":"GBP5 is an interferon-γ-inducible large GTPase that functions as a central integrator of innate immune signaling by promoting NLRP3 inflammasome assembly, facilitating STAT1 nuclear translocation, and exerting antiviral activity through viroporin secretion. GBP5 selectively promotes NLRP3 inflammasome responses to pathogenic bacteria and soluble activators—but not crystalline stimuli—acting as a non-NLR rheostat for caspase-1 activation and IL-1β/IL-18 maturation, with Gbp5-knockout mice showing pronounced defects in inflammasome-dependent inflammation [PMID:22461501]. GBP5 physically binds STAT1 and promotes its nuclear translocation to amplify downstream cytokine transcription and innate lymphoid cell expansion, functioning as a co-facilitator rather than a direct transcription factor [PMID:40055493]. During RSV infection, GBP5 localizes to the Golgi via its C-terminal isoprenylation motif (C583) and promotes extracellular secretion of the SH viroporin through a KRT9-dependent bridging mechanism, while the viral G protein counteracts GBP5 by inducing DZIP3-mediated K48-ubiquitination and proteasomal degradation [PMID:32796072, PMID:39835811]."},"prefetch_data":{"uniprot":{"accession":"Q96PP8","full_name":"Guanylate-binding protein 5","aliases":["GBP-TA antigen","GTP-binding protein 5","GBP-5","Guanine nucleotide-binding protein 5"],"length_aa":586,"mass_kda":66.6,"function":"Interferon (IFN)-inducible GTPase that plays important roles in innate immunity against a diverse range of bacterial, viral and protozoan pathogens (By similarity). Hydrolyzes GTP, but in contrast to other family members, does not produce GMP (PubMed:20180847). 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). As an activator of NLRP3 inflammasome assembly: promotes selective NLRP3 inflammasome assembly in response to microbial and soluble, but not crystalline, agents (PubMed:22461501). 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:26996307, PubMed:31091448) Antigenic tumor-specific truncated splice form","subcellular_location":"Cytoplasmic vesicle membrane; Golgi apparatus membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96PP8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GBP5","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GBP5","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":"606416","title":"NLR FAMILY, PYRIN DOMAIN-CONTAINING 3; NLRP3","url":"https://www.omim.org/entry/606416"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":17.1},{"tissue":"lymphoid tissue","ntpm":40.5}],"url":"https://www.proteinatlas.org/search/GBP5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96PP8","domains":[{"cath_id":"3.40.50.300","chopping":"12-155_172-305","consensus_level":"high","plddt":89.0683,"start":12,"end":305},{"cath_id":"1.20.1000.10","chopping":"310-497","consensus_level":"medium","plddt":94.6593,"start":310,"end":497}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PP8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PP8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PP8-F1-predicted_aligned_error_v6.png","plddt_mean":86.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GBP5","jax_strain_url":"https://www.jax.org/strain/search?query=GBP5"},"sequence":{"accession":"Q96PP8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PP8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PP8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PP8"}},"corpus_meta":[{"pmid":"22461501","id":"PMC_22461501","title":"GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.","date":"2012","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22461501","citation_count":413,"is_preprint":false},{"pmid":"36367676","id":"PMC_36367676","title":"GBP5 exacerbates rosacea-like skin inflammation by skewing macrophage polarization towards M1 phenotype through the NF-κB signalling pathway.","date":"2022","source":"Journal of the European Academy of Dermatology and Venereology : JEADV","url":"https://pubmed.ncbi.nlm.nih.gov/36367676","citation_count":64,"is_preprint":false},{"pmid":"28376501","id":"PMC_28376501","title":"Inducible GBP5 Mediates the Antiviral Response via Interferon-Related Pathways during Influenza A Virus Infection.","date":"2017","source":"Journal of innate immunity","url":"https://pubmed.ncbi.nlm.nih.gov/28376501","citation_count":61,"is_preprint":false},{"pmid":"12396730","id":"PMC_12396730","title":"Murine GBP-5, a new member of the murine guanylate-binding protein family, is coordinately regulated with other GBPs in vivo and in vitro.","date":"2002","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/12396730","citation_count":46,"is_preprint":false},{"pmid":"32796072","id":"PMC_32796072","title":"GBP5 Is an Interferon-Induced Inhibitor of Respiratory Syncytial Virus.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32796072","citation_count":43,"is_preprint":false},{"pmid":"15175044","id":"PMC_15175044","title":"GBP-5 splicing variants: New guanylate-binding proteins with tumor-associated expression and antigenicity.","date":"2004","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15175044","citation_count":42,"is_preprint":false},{"pmid":"33608513","id":"PMC_33608513","title":"GBP5 drives malignancy of glioblastoma via the Src/ERK1/2/MMP3 pathway.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33608513","citation_count":41,"is_preprint":false},{"pmid":"37482570","id":"PMC_37482570","title":"Sinomenine ameliorates collagen-induced arthritis in mice by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling pathways.","date":"2023","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/37482570","citation_count":40,"is_preprint":false},{"pmid":"34958688","id":"PMC_34958688","title":"GBP5 promotes liver injury and inflammation by inducing hepatocyte apoptosis.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34958688","citation_count":33,"is_preprint":false},{"pmid":"38229660","id":"PMC_38229660","title":"The IRF1/GBP5 axis promotes osteoarthritis progression by activating chondrocyte 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Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40636987","citation_count":4,"is_preprint":false},{"pmid":"37434847","id":"PMC_37434847","title":"The expression panel of CXCL9, GBP5, and IFNG is a potential pan-cancer biomarker to predict immunotherapy response.","date":"2023","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/37434847","citation_count":4,"is_preprint":false},{"pmid":"39515806","id":"PMC_39515806","title":"Knockdown of GBP5 alleviates renal damage caused by psoriasis by regulating NF-κB/STAT3 pathway.","date":"2024","source":"Allergologia et immunopathologia","url":"https://pubmed.ncbi.nlm.nih.gov/39515806","citation_count":4,"is_preprint":false},{"pmid":"35502666","id":"PMC_35502666","title":"GBP5 and ACSS3: two potential biomarkers of high-grade ovarian cancer identified through downstream analysis of microarray data.","date":"2022","source":"Journal of biomolecular structure & 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Gbp5-/- mice show pronounced caspase-1 and IL-1β/IL-18 cleavage defects in vitro and impaired Nlrp3-dependent inflammatory responses in vivo, establishing GBP5 as a non-NLR/ALR rheostat for NLRP3 inflammasome activation.\",\n      \"method\": \"Gbp5 knockout mouse generation, in vitro macrophage caspase-1/IL-1β/IL-18 cleavage assays, in vivo infection models, genetic epistasis with Nlrp3\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — knockout mouse with multiple orthogonal readouts, epistasis with NLRP3, replicated across in vitro and in vivo settings; foundational paper with >400 citations\",\n      \"pmids\": [\"22461501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GBP5 inhibits influenza A virus replication by interacting with the NF-κB essential modulator (NEMO) complex and stimulating NF-κB signaling, thereby enhancing interferon and proinflammatory cytokine expression.\",\n      \"method\": \"Overexpression and knockdown in A549 cells, co-immunoprecipitation with NEMO, viral replication assays, cytokine measurement\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — single lab, Co-IP with NEMO plus functional KD/OE assays with defined antiviral phenotype\",\n      \"pmids\": [\"28376501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GBP5 inhibits RSV replication by promoting secretion of the RSV small hydrophobic (SH) viroporin protein via microvesicles, reducing its intracellular levels. Golgi localization (dependent on the C-terminal isoprenylation motif, C583) but not GTPase activity is required for this antiviral function. RSV G protein counteracts GBP5 by upregulating the E3 ubiquitin ligase DZIP3, which degrades GBP5 via K48-linked ubiquitination and the proteasome.\",\n      \"method\": \"C-terminal mutants (GBP5-C583A, GBP5-ΔC) and GTPase-dead mutants, subcellular localization imaging, RSV replication assays, DZIP3 overexpression and siRNA knockdown, proteasome inhibitor experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structure-function mutagenesis, localization studies with functional consequence, defined E3 ligase mechanism, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32796072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP5 promotes GBM cell proliferation, migration, and invasion through the Src/ERK1/2/MMP3 signaling axis. Silencing GBP5 by RNA interference impairs tumor growth and prolongs survival in mouse GBM models.\",\n      \"method\": \"RNA interference knockdown, overexpression, in vitro proliferation/migration/invasion assays, in vivo mouse tumor model, western blotting for Src/ERK1/2/MMP3 pathway\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO/KD with defined cellular and in vivo phenotypes and pathway identification, single lab\",\n      \"pmids\": [\"33608513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP5 knockdown in TNBC cells suppresses cellular migration, IFN-γ/STAT1 and TNF-α/NF-κB signaling, and PD-L1 expression, indicating GBP5 regulates metastatic potential and immune checkpoint ligand expression via these signaling axes.\",\n      \"method\": \"siRNA knockdown in TNBC cell lines, Transwell migration assay, western blotting for STAT1/NF-κB pathways and PD-L1, GSEA computational analysis\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — KD with multiple pathway readouts, single lab with functional and signaling data\",\n      \"pmids\": [\"33916322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP5 induces hepatocyte apoptosis through activation of both the calpain/caspase-12/caspase-3 (intrinsic) and TNFα/caspase-8/caspase-3 (extrinsic) pathways. Liver-specific overexpression of GBP5 is sufficient to induce liver injury, while Gbp5 knockout ameliorates GalN/LPS-induced liver injury.\",\n      \"method\": \"Gbp5 knockout mice, liver-specific adenoviral overexpression, GalN/LPS injury model, calpain inhibitor and caspase-3 inhibitor rescue experiments, western blotting\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — gain- and loss-of-function in vivo with pharmacological rescue of specific apoptotic pathway nodes, multiple orthogonal mechanistic approaches\",\n      \"pmids\": [\"34958688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GBP5 transcription is directly activated by the transcription factor BATF, which binds the GBP5 promoter, thereby promoting NLRP3 inflammasome activation and IL-1β/IL-18 production in sepsis-associated liver injury.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter reporter assays, GBP5 overexpression in LPS-induced SALI model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay establish direct transcriptional regulation; single lab\",\n      \"pmids\": [\"34042221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GBP5 knockdown suppresses M1 macrophage polarization in part by repressing NF-κB signaling pathway activation, reducing expression of IL-6, iNOS, and TNF-α.\",\n      \"method\": \"GBP5 siRNA in THP-1 cells and intradermal injection in mouse rosacea model, M1 marker gene expression analysis, NF-κB pathway western blotting\",\n      \"journal\": \"Journal of the European Academy of Dermatology and Venereology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — siRNA KD with defined macrophage polarization phenotype and NF-κB pathway readout, in vitro and in vivo\",\n      \"pmids\": [\"36367676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IRF1 binds directly to the GBP5 promoter to enhance its transcription, and GBP5 in turn activates the NLRP3 inflammasome pathway to promote chondrocyte pyroptosis in osteoarthritis. Co-transfection with ad-IRF1 and siGBP5 demonstrates epistatic relationship.\",\n      \"method\": \"Dual luciferase reporter gene assay, chromatin immunoprecipitation (ChIP), siRNA and overexpression plasmid transfection, flow cytometry for pyroptosis, ELISA for IL-1β/IL-18\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay confirm direct IRF1-GBP5 promoter interaction; epistasis by co-transfection; single lab\",\n      \"pmids\": [\"38229660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GBP5 is regulated by the IFNγ-JAK1-STAT1 axis and in turn induces CXCL8 expression; CXCL8 then feeds back to activate JAK1-STAT1 signaling, forming a positive feedback loop in gastric cancer cells.\",\n      \"method\": \"RNA-sequencing, western blotting, qPCR in gastric cancer cell lines, pathway inhibition experiments\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RNA-seq plus functional validation of feedback loop, single lab\",\n      \"pmids\": [\"37168340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sinomenine directly binds GBP5 (KD = 3.486 µM as measured by binding affinity assay) and suppresses GBP5/P2X7R-NLRP3 pathway activity, reducing IL-1β and IL-18 production in macrophages and CIA mice.\",\n      \"method\": \"Solvent-induced protein precipitation (SIP) assay, molecular docking simulation, proteomics, binding affinity assay (KD determination), siRNA knockdown, western blotting\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding measured by affinity assay with multiple orthogonal methods; single lab\",\n      \"pmids\": [\"37482570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GBP5 is transcriptionally regulated by HDAC3 in macrophages; HDAC3 overexpression upregulates GBP5 reporter activity, while HDAC3 conditional knockout reduces IFN-γ-induced GBP5 transcription, and this reduction is linked to decreased NLRP3 inflammasome activation.\",\n      \"method\": \"Conditional knockout of Hdac3 in CX3CR1+ cells, RNA sequencing, GBP5 reporter assay with HDAC3 overexpression, RNA-seq validation, RGFP966 inhibitor treatment\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay and conditional KO with RNA-seq mechanistic data; single lab\",\n      \"pmids\": [\"38903915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GBP5 induces canonical pyroptosis in ovarian cancer cells through the JAK2/STAT1 pathway, and high GBP5-expressing cancer cells upregulate CXCL9/10/11, remodeling the tumor immune microenvironment toward increased M1 macrophage infiltration.\",\n      \"method\": \"GBP5 overexpression/knockdown in ovarian cancer cells and patient-derived organoids, invasion/migration assays, JAK2/STAT1 pathway western blotting, co-culture immune assays, immunohistochemistry\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway western blotting with gain/loss of function and organoid model; single lab\",\n      \"pmids\": [\"38817865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GBP5 binds to STAT1 and facilitates its nuclear translocation, thereby enhancing STAT1 transcriptional activity and expression of downstream cytokines that drive innate lymphoid cell expansion in colitis. GBP5 does not directly drive gene transcription but acts as a co-facilitator of STAT1 activity.\",\n      \"method\": \"Co-immunoprecipitation (GBP5-STAT1 interaction), nuclear fractionation, Gbp5 knockout mouse colitis model, GBP5-deficient THP-1 transcriptomics, STAT1 overexpression rescue experiment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP plus nuclear fractionation establishing mechanism, KO mouse with defined ILC phenotype, rescue by STAT1 overexpression; multiple orthogonal methods\",\n      \"pmids\": [\"40055493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT9 is required for GBP5-mediated RSV-SH protein transport and antiviral activity. GBP5 acts as a bridge between KRT9 and RSV-SH protein; KRT9 directly interacts with GBP5 (but not RSV-SH), and a GBP5-binding domain was mapped on KRT9. Silencing KRT9 abrogates GBP5 and IFN-γ antiviral effects.\",\n      \"method\": \"Affinity mass spectrometry, co-immunoprecipitation, siRNA knockdown of KRT9, RSV replication assays, domain mapping experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity MS plus Co-IP and KD with functional antiviral readout; single lab building on prior mechanistic study\",\n      \"pmids\": [\"39835811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ERRγ binds to the GBP5 promoter to inhibit GBP5 transcription, thereby suppressing NLRP3 inflammasome assembly and pyroptosis in cardiomyocytes after myocardial infarction. Overexpression of GBP5 reverses the protective effects of ERRγ overexpression.\",\n      \"method\": \"Cardiomyocyte-specific ERRγ overexpression in vivo, GBP5 promoter binding assay, GBP5 overexpression epistasis experiment, NLRP3 inflammasome assembly assays, cardiac function measurements\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter binding plus epistasis (GBP5 overexpression reverses ERRγ protection) in vivo; single lab\",\n      \"pmids\": [\"40636987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Murine GBP5 encodes a 590 amino acid protein with GTP-binding motifs conserved with human GBP-1 and a C-terminal isoprenylation sequence. An alternatively spliced form lacking the second GTP-binding motif and the isoprenylation site was identified, indicating structural and functional diversity.\",\n      \"method\": \"cDNA cloning, sequence analysis, RNase protection assay, genomic mapping\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — molecular cloning with domain identification; foundational structural characterization\",\n      \"pmids\": [\"12396730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human GBP5 is expressed as at least three splice variants (GBP-5a, -5b, -5ta) producing two proteins; GBP-5ta lacks the C-terminal 97 aa including the isoprenylation site. Protein expression in normal tissue is restricted to peripheral blood monocytes, while both isoforms are expressed in CTCL and melanoma cell lines.\",\n      \"method\": \"RT-PCR, western blotting with isoform-specific antibodies, SEREX immunogenicity testing\",\n      \"journal\": \"Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — protein-level isoform characterization with antibody validation; localization to monocytes established by western blot\",\n      \"pmids\": [\"15175044\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GBP5 is an IFN-γ-inducible large GTPase that functions as a rheostat for NLRP3 inflammasome assembly by promoting selective responses to soluble (not crystalline) activators and pathogenic bacteria; it physically binds STAT1 and facilitates its nuclear translocation to amplify downstream cytokine expression, localizes to the Golgi via its C-terminal isoprenylation motif (required for antiviral activity against RSV by promoting SH viroporin secretion), activates both extrinsic and intrinsic apoptosis pathways in hepatocytes, and is transcriptionally regulated by BATF, IRF1, HDAC3, and ERRγ, while being targeted for K48-ubiquitin-mediated proteasomal degradation by the E3 ligase DZIP3 during RSV infection.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GBP5 is an interferon-γ-inducible large GTPase that functions as a central integrator of innate immune signaling by promoting NLRP3 inflammasome assembly, facilitating STAT1 nuclear translocation, and exerting antiviral activity through viroporin secretion. GBP5 selectively promotes NLRP3 inflammasome responses to pathogenic bacteria and soluble activators—but not crystalline stimuli—acting as a non-NLR rheostat for caspase-1 activation and IL-1β/IL-18 maturation, with Gbp5-knockout mice showing pronounced defects in inflammasome-dependent inflammation [PMID:22461501]. GBP5 physically binds STAT1 and promotes its nuclear translocation to amplify downstream cytokine transcription and innate lymphoid cell expansion, functioning as a co-facilitator rather than a direct transcription factor [PMID:40055493]. During RSV infection, GBP5 localizes to the Golgi via its C-terminal isoprenylation motif (C583) and promotes extracellular secretion of the SH viroporin through a KRT9-dependent bridging mechanism, while the viral G protein counteracts GBP5 by inducing DZIP3-mediated K48-ubiquitination and proteasomal degradation [PMID:32796072, PMID:39835811].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Cloning of murine GBP5 established it as a GTP-binding protein with a C-terminal isoprenylation motif and alternative splicing producing isoforms with distinct domain architectures, providing the first structural framework for functional studies.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and RNase protection assay in mouse\",\n      \"pmids\": [\"12396730\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic or GTPase activity measured\", \"Functional consequence of alternative splicing unknown\", \"No human ortholog characterized at protein level yet\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of three human GBP5 splice variants and restriction of protein expression to peripheral blood monocytes in normal tissue established the cell-type specificity relevant to its later-discovered innate immune functions.\",\n      \"evidence\": \"RT-PCR, isoform-specific western blotting in normal and tumor cell lines\",\n      \"pmids\": [\"15175044\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression in other immune cell types not surveyed comprehensively\", \"Functional differences between GBP-5a/5b/5ta isoforms not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The central question of whether GBP5 has a defined innate immune effector function was answered: GBP5 selectively promotes NLRP3 inflammasome assembly in response to bacteria and soluble agents but not crystalline activators, establishing it as the first non-NLR/non-ALR rheostat for inflammasome gating.\",\n      \"evidence\": \"Gbp5 knockout mice, macrophage caspase-1/IL-1β/IL-18 cleavage assays, in vivo infection models, genetic epistasis with Nlrp3\",\n      \"pmids\": [\"22461501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which GBP5 distinguishes soluble from crystalline activators unknown\", \"Direct physical interaction with NLRP3 or ASC not demonstrated\", \"Whether GTPase activity is required for inflammasome function untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"GBP5's antiviral repertoire was extended beyond inflammasome activation when it was shown to inhibit influenza A virus replication by interacting with NEMO and stimulating NF-κB signaling, revealing a second effector axis.\",\n      \"evidence\": \"Co-immunoprecipitation with NEMO, knockdown and overexpression in A549 cells, viral replication assays\",\n      \"pmids\": [\"28376501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NEMO interaction not confirmed by reciprocal IP or endogenous pull-down\", \"Whether GTPase or isoprenylation motif is needed for NF-κB activation unknown\", \"Single cell line tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The mechanism of GBP5 antiviral activity against RSV was resolved: GBP5 promotes secretion of the RSV SH viroporin via microvesicles, requiring Golgi localization through C583 isoprenylation but not GTPase activity, while RSV counteracts GBP5 through DZIP3-mediated K48-ubiquitination and proteasomal degradation.\",\n      \"evidence\": \"C-terminal and GTPase-dead mutants, subcellular imaging, RSV replication assays, DZIP3 overexpression/siRNA, proteasome inhibitor rescue\",\n      \"pmids\": [\"32796072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of cargo receptor or vesicle machinery linking GBP5 to microvesicle secretion unknown\", \"Whether DZIP3-mediated degradation occurs during other viral infections not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies established that GBP5 transcription is directly regulated by BATF (activating) at the promoter and that GBP5 can activate both intrinsic (calpain/caspase-12/caspase-3) and extrinsic (TNFα/caspase-8/caspase-3) apoptosis in hepatocytes, broadening its cell-death effector functions beyond pyroptosis.\",\n      \"evidence\": \"ChIP and promoter reporter assays for BATF–GBP5 promoter; Gbp5 KO mice and liver-specific adenoviral overexpression in GalN/LPS injury model with calpain and caspase-3 inhibitor rescue\",\n      \"pmids\": [\"34042221\", \"34958688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether apoptosis induction requires GTPase activity or isoprenylation unknown\", \"Mechanism linking GBP5 to calpain activation not defined at molecular level\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"GBP5 was placed in oncogenic and immune-evasion signaling: it promotes GBM tumor growth via Src/ERK1/2/MMP3 and sustains PD-L1 expression in TNBC through IFNγ/STAT1 and TNFα/NF-κB axes, indicating context-dependent pro-tumorigenic roles.\",\n      \"evidence\": \"siRNA/overexpression in GBM and TNBC cell lines, in vivo mouse GBM tumor model, Transwell migration, western blotting for pathway components\",\n      \"pmids\": [\"33608513\", \"33916322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates or binding partners mediating Src or ERK activation not identified\", \"Whether inflammasome function contributes to tumor phenotypes untested\", \"Single-lab studies for each tumor type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two additional transcriptional inputs to GBP5 were defined—IRF1 directly activates the GBP5 promoter to drive NLRP3-mediated chondrocyte pyroptosis, and GBP5 participates in a positive feedback loop with CXCL8 through JAK1-STAT1 signaling—consolidating GBP5 as a convergence node for multiple inflammatory transcription factors.\",\n      \"evidence\": \"ChIP and dual-luciferase reporter for IRF1; RNA-seq and pathway inhibition for CXCL8 feedback loop in gastric cancer cells\",\n      \"pmids\": [\"38229660\", \"37168340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IRF1, BATF, and HDAC3 act combinatorially on the GBP5 promoter unknown\", \"CXCL8 feedback loop demonstrated only in gastric cancer cells\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"HDAC3 was identified as a positive transcriptional regulator of GBP5 in macrophages, linking epigenetic control to inflammasome output, while GBP5 was shown to induce canonical pyroptosis in ovarian cancer cells via JAK2/STAT1 with consequent CXCL9/10/11-driven M1 macrophage recruitment.\",\n      \"evidence\": \"Conditional Hdac3 KO in CX3CR1+ cells with RNA-seq and reporter assays; GBP5 OE/KD in ovarian cancer cells and patient-derived organoids with immune co-culture\",\n      \"pmids\": [\"38903915\", \"38817865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HDAC3 acts directly on GBP5 promoter chromatin or indirectly through another factor not resolved\", \"Relative contribution of pyroptosis vs. chemokine secretion to tumor immune remodeling unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The mechanism by which GBP5 amplifies cytokine signaling was resolved: GBP5 physically binds STAT1 and facilitates its nuclear translocation without acting as a transcription factor itself, functioning as a co-facilitator of STAT1 activity that drives innate lymphoid cell expansion in colitis.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, nuclear fractionation, Gbp5 KO mouse colitis model, STAT1 overexpression rescue in GBP5-deficient THP-1 cells\",\n      \"pmids\": [\"40055493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain on GBP5 mediating STAT1 binding not mapped\", \"Whether GBP5 also facilitates nuclear translocation of other STATs unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"KRT9 was identified as the obligate partner bridging GBP5 to RSV-SH protein for antiviral viroporin secretion, with a mapped GBP5-binding domain on KRT9, explaining the cargo-specificity of the GBP5 secretory antiviral pathway. ERRγ was identified as a transcriptional repressor of GBP5 that suppresses inflammasome-mediated cardiomyocyte pyroptosis after myocardial infarction.\",\n      \"evidence\": \"Affinity mass spectrometry and Co-IP for KRT9–GBP5 interaction, KRT9 siRNA abolishing antiviral effect; ERRγ promoter binding assay and in vivo epistasis in cardiomyocytes\",\n      \"pmids\": [\"39835811\", \"40636987\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KRT9–GBP5 interaction occurs in non-RSV antiviral contexts unknown\", \"ERRγ-GBP5 axis demonstrated only in cardiomyocytes; generalizability untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis and direct binding interface for GBP5-NLRP3/ASC interaction, (2) whether GTPase activity is dispensable for all GBP5 functions or only for RSV-related secretion, (3) the integration of multiple transcriptional inputs (BATF, IRF1, HDAC3, ERRγ) at the GBP5 promoter, and (4) the molecular mechanism by which GBP5 distinguishes soluble from crystalline NLRP3 activators.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure or cryo-EM of GBP5 alone or in complex\", \"No reconstituted in vitro inflammasome assembly with purified GBP5\", \"Isoform-specific functions of GBP-5a/5b/5ta remain untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [16, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 7, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 9, 13]}\n    ],\n    \"complexes\": [\n      \"NLRP3 inflammasome\"\n    ],\n    \"partners\": [\n      \"NLRP3\",\n      \"STAT1\",\n      \"NEMO\",\n      \"DZIP3\",\n      \"KRT9\",\n      \"BATF\",\n      \"IRF1\",\n      \"HDAC3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}