Affinage

GBP4

Guanylate-binding protein 4 · UniProt Q96PP9

Round 2 corrected
Length
640 aa
Mass
73.2 kDa
Annotated
2026-04-28
26 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GBP4 is an IFN-γ-inducible dynamin-superfamily GTPase that functions as a critical mediator of inflammasome activation and innate immune defense against intracellular bacteria. It exhibits a distinctive nucleocytoplasmic distribution, engages in heterodimerization with prenylated GBP family members to regulate intracellular trafficking, and activates inflammasomes in a GTPase activity– and ASC-dependent manner to drive prostaglandin D2–mediated bacterial clearance by neutrophils (PMID:17266443, PMID:21151871, PMID:27363812). GBP4 physically interacts with NLRP3 and positively regulates NLRP3 expression and downstream pyroptotic signaling, while also functioning in non-canonical inflammasome pathways leading to gasdermin pore formation (PMID:41549441, PMID:41220568). Beyond inflammasome biology, GBP4 modulates antigen cross-presentation and CD8+ T cell responses in both infection and cancer contexts, with its expression regulated epigenetically through DNA methylation and post-transcriptionally via YTHDF1-mediated m6A recognition (PMID:40607809, PMID:39110249, PMID:39806403).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 Low

    Genomic characterization of the GBP locus revealed that GBP4 lacks canonical GAS and ISRE promoter elements, raising the question of how its expression is regulated relative to other interferon-stimulated GBPs.

    Evidence In silico promoter and genomic analysis of the human and murine GBP gene clusters

    PMID:16689661

    Open questions at the time
    • Computational analysis only; no experimental promoter validation
    • Does not address tissue-specific regulatory elements
    • Functional consequence of absent GAS/ISRE elements untested
  2. 2007 Medium

    Direct imaging established that GBP4 has a unique nucleocytoplasmic distribution distinct from other GBPs and is selectively induced by IFN-γ but not TNF-α or IL-1β, defining its subcellular niche and activation signal.

    Evidence Time-lapse microscopy and fluorescence analysis of GFP-tagged GBP4 in endothelial cells with cytokine stimulation

    PMID:17266443

    Open questions at the time
    • Localization studied only in endothelial cells; generalizability to immune cells unknown
    • Mechanism of nucleocytoplasmic partitioning not identified
  3. 2010 Medium

    Demonstration that GBP4 participates in a heterodimerization network with prenylated GBPs (GBP-1, -2, -5) explained how a non-prenylated GBP can be redirected to membrane compartments, establishing a trafficking regulation mechanism within the family.

    Evidence Co-immunoprecipitation, yeast two-hybrid, and fluorescence complementation assays

    PMID:21151871

    Open questions at the time
    • Functional consequence of GBP4 relocalization not tested in infection models
    • Stoichiometry and structural basis of heterodimers undefined
  4. 2016 High

    In vivo genetic studies in zebrafish demonstrated that Gbp4's GTPase activity is indispensable for inflammasome activation and that Gbp4 drives ASC-dependent prostaglandin D2 biosynthesis for neutrophil-mediated bacterial clearance, establishing the first direct antimicrobial mechanism for GBP4.

    Evidence Zebrafish Salmonella infection model with morpholino knockdown, GTPase-dead mutants, Asc epistasis, and prostaglandin D2 measurement

    PMID:27363812

    Open questions at the time
    • Zebrafish Gbp4 contains a C-terminal CARD domain absent in human GBP4; direct translational relevance uncertain
    • How GTPase activity couples to inflammasome assembly mechanistically unresolved
  5. 2024 Medium

    Epigenetic editing revealed that DNA hypomethylation drives GBP4 overexpression in pancreatic cancer, which promotes CD8+ T cell infiltration but simultaneously induces immune checkpoint upregulation and T cell exhaustion, uncovering a dual role in tumor immunity.

    Evidence dCas9-SunTag-DNMT3A targeted methylation, chemotaxis assays, and primary organoid T cell killing assays

    PMID:39110249

    Open questions at the time
    • In vivo tumor model validation not reported
    • Direct mechanism linking GBP4 to checkpoint gene upregulation not identified
  6. 2025 Medium

    Multiple studies converged to define GBP4's roles in inflammasome signaling, antigen presentation, and macrophage polarization: YTHDF1-mediated m6A modification was shown to enhance GBP4 translation and promote M1 macrophage polarization; GBP4 was placed in a non-canonical inflammasome pathway downstream of type I IFN via Natterin/CRFB1; and Gbp4 knockout in mice impaired endothelial antigen cross-presentation, altering T cell function in cerebral malaria.

    Evidence Mouse acute lung injury model with YTHDF1/GBP4 knockdown; zebrafish CRISPR natterin knockout with epistasis; Gbp4/Irgb6 double-knockout mice with RNA-seq and T cell functional assays

    PMID:39806403 PMID:40607809 PMID:41220568

    Open questions at the time
    • M1 polarization mechanism downstream of GBP4 not delineated
    • Relative contributions of Gbp4 versus Irgb6 in antigen presentation not fully resolved
    • Whether human GBP4 functions equivalently in non-canonical inflammasome activation untested
  7. 2026 Medium

    Physical interaction between GBP4 and NLRP3 was demonstrated, and GBP4 knockdown decreased NLRP3 expression during LPS-induced inflammation, establishing GBP4 as an upstream regulator of canonical NLRP3 inflammasome signaling in human cells.

    Evidence Co-immunoprecipitation and shRNA knockdown in human spermatogonial stem cells under LPS stimulation

    PMID:41549441

    Open questions at the time
    • Reciprocal Co-IP not reported
    • Whether GBP4 stabilizes NLRP3 protein or regulates its transcription not distinguished
    • Single cell type (spermatogonial stem cells) limits generalizability

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of GBP4 interaction with NLRP3 and other inflammasome components, the precise GTPase-dependent conformational changes driving inflammasome assembly, and whether human GBP4 (lacking a CARD domain) activates inflammasomes through the same mechanism as zebrafish Gbp4 remain open questions.
  • No crystal structure or cryo-EM structure of GBP4 or GBP4-NLRP3 complex
  • No reconstituted in vitro inflammasome activation assay with purified human GBP4
  • Mechanism linking GTPase cycle to effector recruitment unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3
Partners
ASCGBP1GBP2GBP5NLRP3YTHDF1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Human GBP4 (HuGBP-4) displays a distinct nucleocytoplasmic distribution in endothelial cells, unlike GBP-1, GBP-3, and GBP-5 which are exclusively cytoplasmic. GBP-4 is robustly induced by IFN-γ but not by TNF-α or IL-1β, and is never detected in the Golgi apparatus even upon IFN-γ and aluminum fluoride treatment, distinguishing it from GBP-1 and GBP-2. Time-lapse microscopy and fluorescence analyses of GFP-tagged HuGBPs, immunofluorescence, cytokine stimulation experiments Journal of interferon & cytokine research Medium 17266443
2005 GBPs, including GBP4, belong to the dynamin superfamily and possess unique GTPase activity capable of hydrolyzing GTP to both GDP and GMP, distinguishing them from other large GTPases. Biochemical GTPase assays, structural analysis review of the GBP family Journal of interferon & cytokine research Low 16108726
2006 Genomic analysis confirmed that human GBP4 is located in the GBP gene cluster on chromosome 1 and, unlike most other human GBPs, lacks canonical GAS (IFN-γ activation site) and ISRE (IFN-stimulated response element) promoter elements, suggesting it may not be fully IFN-responsive in the same manner as other family members. In silico genomic and promoter analysis of human and murine GBP gene clusters Journal of interferon & cytokine research Low 16689661
2010 GBP-4 (non-prenylated) can be redirected to the subcellular compartment occupied by prenylated GBPs (GBP-1, GBP-2, GBP-5) through heterodimerization, demonstrating that GBP-4 participates in a hierarchical heterodimerization network that regulates intracellular trafficking of GBP family members. Co-immunoprecipitation, yeast two-hybrid analysis, fluorescence complementation assays PloS one Medium 21151871
2016 Zebrafish Gbp4, an IFN-γ-inducible GTPase harboring a C-terminal CARD domain, is required for inflammasome-dependent clearance of Salmonella Typhimurium by neutrophils in vivo. Gbp4 requires the inflammasome adaptor Asc for its antibacterial function despite having its own CARD domain. The GTPase activity of Gbp4 is indispensable for inflammasome activation. Mechanistically, neutrophil recruitment occurs through Gbp4-independent production of CXCL8 and leukotriene B4, while bacterial clearance is mediated through Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. In vivo zebrafish infection model, genetic loss-of-function (morpholino/mutants), GTPase-dead mutant analysis, prostaglandin D2 measurement, CXCL8 and LTB4 measurement, Asc epistasis experiments Nature communications High 27363812
2024 DNA hypo-methylation in regulatory regions of GBP4 drives its overexpression in pancreatic ductal carcinoma. GBP4 overexpression promotes infiltration of CD8+ T cells but simultaneously induces upregulation of immune checkpoint genes and T cell exhaustion. Targeted methylation of GBP4 regulatory loci using a dCas9-SunTag-DNMT3A system reduced GBP4 expression, validating its epigenetic regulation. Targeted DNA methylation (dCas9-SunTag-DNMT3A), chemotaxis assays, in vitro T cell killing assays with primary organoids, expression analysis Cancer immunology, immunotherapy Medium 39110249
2025 YTHDF1 recognizes m6A modification sites on GBP4 mRNA and enhances GBP4 protein expression, which in turn promotes M1 macrophage polarization. Knockdown of YTHDF1 reduced GBP4 expression and attenuated M1 polarization in an acute lung injury model. Mouse ALI model, GBP4 overexpression/knockdown, YTHDF1 knockdown, m6A site identification, macrophage polarization assays Respiratory research Medium 39806403
2025 In a murine experimental cerebral malaria model, Gbp4 (downstream of IFN-γ but not IFN-α/β signaling) contributes to pathology by regulating antigen cross-presentation in endothelial cells of the olfactory bulb. Double knockout of Gbp4 and Irgb6 resulted in increased CD4+ and CD8+ T cell infiltration with reduced T cell functionality and impaired antigen presentation, leading to enhanced parasite accumulation and improved host survival. Gbp4 and Irgb6 single and double knockout mice, transcriptomic profiling (RNA-seq), T cell functional assays, flow cytometry, antigen presentation assays mBio Medium 40607809
2025 In zebrafish, GBP4 functions downstream of type I IFN (IFN-φ1) signaling via the receptor CRFB1 during Salmonella Typhimurium challenge. Natterin deficiency abolished GBP4 expression and prevented proteolytic maturation of inflammatory caspases Caspy and Caspy2, placing GBP4 in the pathway: Natterin → IFN-φ1/CRFB1 → GBP4 → non-canonical inflammasome activation → Caspy2 maturation → gasdermin pore formation. CRISPR/Cas9 knockout of natterin, IFN-I neutralizing antibody, RT-qPCR, Western blotting, immunohistochemistry, survival assays Frontiers in cellular and infection microbiology Medium 41220568
2026 GBP4 physically interacts with NLRP3 in human spermatogonial stem cells, as demonstrated by co-immunoprecipitation. GBP4 shRNA knockdown decreased NLRP3 expression under LPS-induced inflammatory conditions, indicating GBP4 acts upstream to regulate NLRP3-dependent pyroptosis (caspase-1 and gasdermin D activation) in these cells. Co-immunoprecipitation (Co-IP), GBP4 shRNA knockdown, RNA-Seq, KEGG pathway and PPI analysis, LPS-induced pyroptosis model Asian journal of andrology Medium 41549441

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 131 16689661
2010 Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner. PloS one 111 21151871
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2016 Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins. Nature communications 102 27363812
2013 CBFβ stabilizes HIV Vif to counteract APOBEC3 at the expense of RUNX1 target gene expression. Molecular cell 102 23333304
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2007 Unique features of different members of the human guanylate-binding protein family. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 88 17266443
2010 New genetic associations detected in a host response study to hepatitis B vaccine. Genes and immunity 69 20237496
2022 NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia. Nature immunology 46 36138187
2005 The guanylate-binding proteins (GBPs): proinflammatory cytokine-induced members of the dynamin superfamily with unique GTPase activity. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 46 16108726
2014 Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02_AG on human brain microvascular endothelial cells: implications for blood-brain barrier dysfunction. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 33 24667918
1998 Cloning, expression, and characterization of a novel guanylate-binding protein, GBP3 in murine erythroid progenitor cells. Biochimica et biophysica acta 21 9659399
2018 Integrating CNVs into meta-QTL identified GBP4 as positional candidate for adult cattle stature. Functional & integrative genomics 19 29737453
2024 Guanylate binding protein 4 shapes an inflamed tumor microenvironment and identifies immuno-hot tumors. Journal of cancer research and clinical oncology 12 38347243
2006 High conservation of the differentially amplified MPA2 satellite DNA family in parthenogenetic root-knot nematodes. Gene 12 16765538
2024 DNA hypo-methylation and expression of GBP4 induces T cell exhaustion in pancreatic cancer. Cancer immunology, immunotherapy : CII 10 39110249
2025 YTHDF1-mediated m6A modification of GBP4 promotes M1 macrophage polarization in acute lung injury. Respiratory research 9 39806403
2013 HIV gp120 induced gene expression signatures in vaginal epithelial cells. Microbes and infection 9 23867815
2025 EndoMAP.v1 charts the structural landscape of human early endosome complexes. Nature 6 40437099
2025 Genetic Variants of GBP4: Reduced Risks for Drug-Induced Acute Liver Failure in Non-Finnish European Population. Liver international : official journal of the International Association for the Study of the Liver 1 39868816
2026 NLRP3 activation by lipopolysaccharide (LPS) mediates the pyroptosis of human spermatogonial stem cells via GBP4 regulation. Asian journal of andrology 0 41549441
2025 IFNγ-inducible Gbp4 and Irgb6 contribute to experimental cerebral malaria pathology in the olfactory bulb. mBio 0 40607809
2025 Macrophage-Related GBP4 as a Novel Biomarker for Crohn's Disease: Insights from WGCNA, Mendelian Randomization, and Immunohistochemical Validation. Current topics in medicinal chemistry 0 40776645
2025 Natterin bridges IFN-φ1 and non-canonical inflammasome pathways via CRFB1/Gbp4 to license Caspy2-mediated antibacterial immunity. Frontiers in cellular and infection microbiology 0 41220568