{"gene":"FUT8","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2004,"finding":"FUT8 encodes an α-1,6-fucosyltransferase that catalyzes transfer of fucose from GDP-fucose to the core N-acetylglucosamine of N-glycans via an α-1,6-linkage; knockout of both FUT8 alleles in CHO cells produces completely defucosylated antibodies with ~100-fold enhanced ADCC activity via stronger FcγRIIIa binding.","method":"Sequential homologous recombination knockout in CHO cells; ADCC assay; FcγRIIIa binding assay","journal":"Biotechnology and bioengineering","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct enzymatic knockout with defined biochemical and cellular readouts, replicated in multiple subsequent studies","pmids":["15352059"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of human FUT8 at 2.6 Å resolution reveals three domains: an N-terminal coiled-coil (α-helical) domain, a GT-B fold catalytic domain with a Rossmann fold for donor (GDP-fucose) binding, and a C-terminal SH3 domain. Conserved residues in three regions participate in the Rossmann fold and act as the donor binding site or in catalysis.","method":"X-ray crystallography at 2.6 Å resolution","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional domain identification, foundational structural paper","pmids":["17172260"],"is_preprint":false},{"year":2005,"finding":"FUT8 catalyzes GDP-fucose transfer via a rapid equilibrium random mechanism. The enzyme strongly recognizes the base portion and diphosphoryl group of GDP-β-L-fucose; two conserved neighboring arginine residues play an important role in donor substrate binding.","method":"Recombinant human FUT8 produced in baculovirus-infected insect cells; kinetic analysis; inhibition studies with GDP-fucose derivatives","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with kinetic characterization and substrate analogue inhibition in a single rigorous study","pmids":["16344263"],"is_preprint":false},{"year":2006,"finding":"In Fut8 knockout mice, TGF-β1 receptor activation and signaling are markedly dysregulated, causing overexpression of MMPs (MMP12, MMP13) and downregulation of extracellular matrix proteins such as elastin, contributing to emphysema-like lung destruction. Therapeutic administration of exogenous TGF-β1 rescued the knockout mice from emphysema. Loss of core fucosylation on EGF and PDGF receptors also downregulates receptor-mediated signaling; reintroduction of Fut8 rescues these signaling impairments.","method":"Fut8 knockout mouse model; TGF-β1 rescue experiment; Fut8 gene reintroduction into null cells","journal":"Methods in enzymology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with phenotypic rescue by exogenous ligand and gene reintroduction, multiple receptors tested","pmids":["17132494"],"is_preprint":false},{"year":2006,"finding":"Loss of core fucosylation in Fut8-null mouse cells impairs LRP-1-mediated endocytosis of IGFBP-3, leading to markedly elevated serum IGFBP-3 levels in Fut8-/- mice. Re-introduction of Fut8 restores LRP-1 endocytic activity.","method":"Fut8 knockout mouse model; endocytosis assay; Fut8 gene reintroduction; serum IGFBP-3 measurement","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with functional rescue, defined substrate (LRP-1), and in vivo serum measurement","pmids":["16567404"],"is_preprint":false},{"year":2009,"finding":"Fut8 is required for expression of VEGFR-2; loss of Fut8 in knockout mice suppresses VEGFR-2 mRNA and protein expression, increases ceramide levels (an apoptosis inducer), and increases TUNEL-positive septal cells, contributing to emphysema-like lung changes.","method":"Fut8 knockout mouse model; siRNA knockdown in A549 and TGP49 cells; TUNEL assay; ceramide measurement","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and siRNA with multiple readouts in a single lab","pmids":["19179362"],"is_preprint":false},{"year":2012,"finding":"Donor substrate GDP-fucose binds FUT8 with guanine specifically recognized by His363 and Asp453, the pyrophosphate contributes major binding affinity, and Arg365 contacts both the β-phosphate and the fucose moiety simultaneously.","method":"STD NMR; surface plasmon resonance; molecular dynamics simulation; structural analogy with cePOFUT","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR epitope mapping and SPR from a single lab without mutagenesis validation of all identified contacts","pmids":["22982178"],"is_preprint":false},{"year":2013,"finding":"Knockdown of Fut8 in PC12 cells promotes neurite formation and induction of neurofilament expression by increasing phospho-Smad2 levels via enhanced activin receptor signaling. α-1,6-Fucosylation on activin receptors negatively regulates activin-mediated signaling (reduced fucosylation on activin receptors in KD cells without changing total receptor expression). Restoration of Fut8 expression rescues these changes, demonstrating Fut8 plays a dual opposing role in TGF-β/activin-mediated signaling.","method":"siRNA knockdown; Fut8 gene restoration; phospho-Smad2 western blot; neurite formation assay; activin receptor inhibition","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and rescue experiments with multiple orthogonal readouts in a single lab","pmids":["23796784"],"is_preprint":false},{"year":2013,"finding":"FUT8 overexpression inhibits hemoglobin production during erythroid differentiation of murine erythroleukemia and K562 human cells. The donor substrate-binding domain and a flexible loop of FUT8 are essential for this inhibitory function. c-Myc and c-Myb positively regulate Fut8 expression; FUT8 shRNA induces hemoglobin production and increases transferrin receptor/glycophorin A-positive cells.","method":"Overexpression and shRNA knockdown; hemoglobin assay; domain/loop mutagenesis; flow cytometry","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain mutagenesis and KD/OE with specific cellular phenotype readout","pmids":["23609441"],"is_preprint":false},{"year":2016,"finding":"FUT8 (mammalian α1,6-fucosyltransferase) is the sole enzyme responsible for GnT-I-independent core fucosylation of high-mannose N-glycans; in HEK293S GnT-I-/- cells, FUT8 knockdown abolishes core fucosylation of Man5GlcNAc2 glycoforms, whereas FUT8 overexpression produces fully core-fucosylated high-mannose glycoforms.","method":"Stable FUT8 knockdown and overexpression in HEK293S GnT-I-/- cells; glycan mass spectrometry analysis of EPO","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-like cell genetic system with mass spectrometry glycan verification in a single rigorous study","pmids":["27008861"],"is_preprint":false},{"year":2017,"finding":"FUT8-mediated core fucosylation of TGF-β receptor complexes facilitates TGF-β binding and enhances downstream signaling in breast carcinoma cells, promoting EMT and invasion. FUT8 knockdown (shRNA or CRISPR) suppresses invasiveness of highly aggressive breast cancer cells and impairs lung metastasis in vivo.","method":"Lentivirus gain-of-function; shRNA/CRISPR loss-of-function; lectin blot; luciferase assay; in vitro ligand binding assay; transwell invasion; mammary fat pad xenograft","journal":"Breast cancer research : BCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical binding assay, functional KD/OE, in vivo model) with defined molecular target (TGF-β receptor)","pmids":["28982386"],"is_preprint":false},{"year":2017,"finding":"FUT8 is a driver of melanoma metastasis; FUT8 silencing suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 are enriched in cell migration proteins including L1CAM; core fucosylation by FUT8 impacts L1CAM cleavage and L1CAM-supported invasion.","method":"In vitro invasion assay; in vivo tumor dissemination model; glycoproteomic identification of FUT8 targets; FUT8 silencing","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo functional studies in patient samples plus identification of molecular target with mechanistic follow-up","pmids":["28609658"],"is_preprint":false},{"year":2020,"finding":"The SH3 domain of FUT8 is essential for enzymatic activity (both in cells and in vitro); His-535 in the SH3 domain is the critical residue for catalytic activity. The SH3 domain also controls FUT8 trafficking to the cell surface. FUT8 binds ribophorin I (RPN1), a subunit of the oligosaccharyltransferase complex, in an SH3-dependent manner; RPN1 knockdown decreases FUT8 activity and core fucose levels, indicating RPN1 stimulates FUT8 activity.","method":"Truncated FUT8 constructs; immunofluorescence; FACS; cell-surface biotinylation; proteomics; LC-ESI-MS; His-535 mutagenesis; RPN1 siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis, multiple orthogonal methods, identified interacting protein with functional validation, single rigorous study","pmids":["32350116"],"is_preprint":false},{"year":2020,"finding":"The α-helical (N-terminal coiled-coil) and SH3 domains of FUT8 are both required for full enzymatic activity and form the basis of FUT8 homodimerization via intermolecular hydrophobic interactions of α-helical domains. In vivo cross-linking experiments show the SH3 domain is positioned in close proximity to the α-helical domain in an intermolecular manner, forming the active quaternary structure.","method":"Domain truncation; site-directed mutagenesis; in vivo disulfide cross-linking; heterologous expression in Sf21/COS-1 cells; SDS-PAGE enzymatic activity assay","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis and cross-linking in a single lab with multiple domain mutants","pmids":["32147455"],"is_preprint":false},{"year":2020,"finding":"FUT8 crystal structures in complex with a donor substrate analog (GDP) and four distinct glycan acceptors reveal: active site loop ordering correlates with increased GDP occupancy (induced-fit binding); binding site complementarity and steric hindrance tune substrate affinity; the G0 biantennary complex N-glycan is preferred. FUT8 structure comparison with other fucosyltransferases identifies conserved and divergent GT-B fold features for donor/acceptor recognition.","method":"X-ray crystallography of multiple FUT8-ligand complexes; active site mutagenesis with kinetic analysis; glycan acceptor library specificity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with active site mutagenesis and kinetic validation in a single rigorous study","pmids":["33004438"],"is_preprint":false},{"year":2020,"finding":"FUT8 overexpression in prostate cancer cells upregulates cell-surface EGFR and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions (castration resistance). Castration in xenograft models induces FUT8 overexpression associated with increased EGFR expression.","method":"Proteomic analysis; FUT8 overexpression; EGFR surface expression measurement; androgen deprivation in vitro and xenograft","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic approach with OE experiment and in vivo model, single lab","pmids":["32085441"],"is_preprint":false},{"year":2020,"finding":"FUT8 core fucosylation of EGFR is required for EGFR overactivation in keratinocytes; FUT8 loss-of-function reduces EGFR/AKT signaling, reduces ligand-induced EGFR dimerization, slows EGF-EGFR complex trafficking to the perinuclear region, and ameliorates psoriasis-like phenotype in a conditional knockout mouse model.","method":"shFUT8; FUT8 gain-of-function; EGFR signaling by western blot; EGFR dimerization assay; trafficking assay; conditional FUT8 KO in IL-23 psoriasis mouse model","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function, gain-of-function, in vivo conditional KO with mechanistic readouts including dimerization and trafficking, multiple orthogonal methods","pmids":["32888953"],"is_preprint":false},{"year":2021,"finding":"FUT8 catalyzes core fucosylation of B7H3 (CD276) N-glycans in TNBC cells, which stabilizes B7H3 protein and maintains its high expression level, contributing to immunosuppression. FUT8 knockdown reduces glycosylated B7H3-mediated immunosuppressive function.","method":"FUT8 knockdown; glycoprotein stability assay; immune functional assay; combination with anti-PDL1 in B7H3-positive tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD experiments with defined substrate (B7H3), protein stability readout, functional immune assay, and in vivo combination therapy, single rigorous study","pmids":["33976130"],"is_preprint":false},{"year":2021,"finding":"FUT8 substrate specificity is regulated by the glycan structure and protein/peptide environment. FUT8 recognizes all sugar units of the G0 N-glycan (shown by STD NMR) and most residues of the Asn-X-Thr sequon. Prior FUT8 binding to GDP is required for optimal N-glycan recognition. The underlying peptide influences fucosylation of paucimannose and high-mannose N-glycans but not complex-type N-glycans.","method":"STD NMR; in vitro FUT8 assay with N-glycopeptide library; CHO cell glycoengineering; glycoproteomic analysis","journal":"ACS catalysis","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR, in vitro enzymatic assay, and cell-based glycoengineering in a single study with multiple orthogonal methods","pmids":["35662980"],"is_preprint":false},{"year":2021,"finding":"FUT8 overexpression increases delivery of MUC1 to the plasma membrane and extracellular release of MUC2 and MUC5AC. Mucins secreted by FUT8-overexpressing cells are more resistant to removal from the cell surface. FUT8 KD causes intracellular MUC1 accumulation and alters the MUC2:MUC5AC ratio. Fut8-/- mice show a thinner proximal colon mucus layer with altered neutral-to-acidic mucin ratio.","method":"FUT8 overexpression/KD in HT29-18N2 cells; mucin trafficking assay; Fut8-/- mouse colonic mucus analysis; mucin resistance assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-based gain/loss-of-function plus Fut8 KO mouse model with specific mechanistic readouts, multiple orthogonal methods","pmids":["36252012"],"is_preprint":false},{"year":2021,"finding":"FUT8 modifies α1,6-fucosylation of IGF-1 receptor (IGF-1R), regulates IGF-1-dependent activation of IGF-1R, and regulates downstream MAPK and PI3K/Akt signaling in trophoblastic cells. FUT8 knockdown suppresses proliferation, EMT, migration and invasion of JAR and JEG-3 cells.","method":"siRNA knockdown; immunoprecipitation; IGF-1R phosphorylation assay; functional cell assays","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP of core-fucosylated IGF-1R combined with functional KD and signaling readouts, single lab","pmids":["30712666"],"is_preprint":false},{"year":2022,"finding":"The FUT8 stem region (two α-helices) is essential for FUT8 multimer (oligomer) formation but not for catalytic activity per se. Loss of the stem region destabilizes FUT8 protein, increases ER localization, and shortens its half-life. The first helix of the stem region is critical for multimer formation.","method":"FUT8 stem deletion mutants expressed in FUT8-KO HEK293 cells; immunoprecipitation; native-PAGE; subcellular localization by immunofluorescence; half-life measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis with multiple structural and functional readouts in a clean KO reconstitution system","pmids":["36336076"],"is_preprint":false},{"year":2023,"finding":"FUT8-mediated core fucosylation is required for amyloid-β oligomer (AβO)-induced pro-inflammatory activation of human iPSC-derived microglia. FUT8/core fucosylation inhibition reduces pro-inflammatory cytokines, suppresses p38MAPK activation, and rectifies phagocytic deficits. p53 binds two consensus sites in the FUT8 promoter and p53 knockdown abolishes FUT8 overexpression in AβO-activated microglia, placing FUT8 downstream of p53 in microglial signaling.","method":"siRNA-mediated FUT8 KD in human iPSC-derived microglia; fucosylation inhibitor; cytokine assay; p38MAPK assay; phagocytosis assay; ChIP-like p53 promoter binding analysis; p53 siRNA","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and pharmacological inhibition with multiple functional readouts plus upstream regulator identification, single lab","pmids":["36692036"],"is_preprint":false},{"year":2023,"finding":"FUT8 inhibition (by FUT8 silencing) causes defucosylation at N104 on B7-H3, which allows HSC70 (HSPA8) to bind the 106-110 SLRLQ motif of B7-H3 and drives lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy (CMA) pathway. A selective small-molecule FUT8 inhibitor FDW028 recapitulates this mechanism and prolongs survival in CRC pulmonary metastasis models.","method":"FUT8 silencing; site-specific glycan mutants (N104); HSC70/LAMP2A co-IP; CMA pathway assay; FDW028 inhibitor characterization; in vivo mouse model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific glycosite mutant, protein interaction validated by IP, pathway mechanism with CMA readout, and pharmacological validation in vivo","pmids":["37537172"],"is_preprint":false},{"year":2023,"finding":"FUT8 regulates TGF-β1-induced pulmonary fibroblast (MRC-5) proliferation, migration and fibrosis by interacting with galectin-3 (Gal-3), as demonstrated by co-immunoprecipitation. FUT8 silencing downregulates Gal-3 expression and inhibits FAK/Akt signaling; Gal-3 overexpression reverses the effects of FUT8 silencing.","method":"Co-immunoprecipitation; siRNA knockdown; western blot; CCK-8; wound healing; bleomycin mouse model with sh-FUT8","journal":"Nan fang yi ke da xue xue bao","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying FUT8-Gal-3 interaction, functional rescue with Gal-3 OE, in vivo mouse model","pmids":["36073215"],"is_preprint":false},{"year":2024,"finding":"FUT8 catalyzes core fucosylation of SEMA7A at N-linked glycosylation sites (Asn 105, 157, 258, 330, and 602) via direct protein-protein interaction. Core fucosylation is required for SEMA7A intracellular trafficking from cytoplasm to cytomembrane. EGF increases SEMA7A binding affinity to FUT8, enhancing fucosylation; TGF-β1 promotes SEMA7A glycosylation via EMT induction.","method":"Co-IP (FUT8-SEMA7A interaction); glycosite-specific mutants; subcellular trafficking assay; EGF/TGF-β1 treatment","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction by Co-IP, specific glycosite identification, trafficking functional assay, single lab","pmids":["38548747"],"is_preprint":false},{"year":2024,"finding":"A selective FUT8 inhibitor with KD = 49 nM binds FUT8 only in the presence of GDP (product of the enzymatic reaction), generates a reactive naphthoquinone methide derivative at the active site that covalently reacts with FUT8 (mechanism-based inhibition). Prodrug derivatization enables cellular suppression of core fucose expression and subsequent EGFR and T-cell signaling.","method":"High-throughput screening; SPR binding assay; mechanistic inhibitor studies; cell-based EGFR and T-cell signaling assays","journal":"Angewandte Chemie (International ed. in English)","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding characterization with mechanistic study plus cell-based validation in a single study","pmids":["39340265"],"is_preprint":false},{"year":2024,"finding":"FUT8 interacts with TMEM67 (a ciliary transition zone component) and catalyzes its core fucosylation, which stabilizes TMEM67 by preventing its degradation via autophagy. Loss of core fucosylation of TMEM67 causes mislocalization from the transition zone. Fut8-deficient mice exhibit ciliary defects in kidney, brain, and trachea.","method":"Mass spectrometry proteomics; Co-IP (FUT8-TMEM67); core fucosylation assay; autophagy degradation assay; Fut8-deficient mouse ciliary phenotype analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct interaction by Co-IP, degradation mechanism established, in vivo KO mouse with specific ciliary phenotype, multiple organs analyzed","pmids":["40728580"],"is_preprint":false},{"year":2024,"finding":"FUT8 upregulates CD36 expression and its core fucosylation level in pericytes, contributing to activation of the mitochondrial-dependent apoptosis signaling pathway and pericyte-myofibroblast transition in AKI-to-CKD progression.","method":"IP and confocal immunofluorescence for CD36 core fucosylation; IRI mouse model; H/R cell model; flow cytometry apoptosis; JC-1 mitochondrial membrane potential","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-based core fucosylation detection of CD36, in vivo and in vitro models with signaling readout, single lab","pmids":["39563263"],"is_preprint":false},{"year":2023,"finding":"Renal tubular epithelial cell-specific deletion of FUT8 ameliorates IRI-induced renal interstitial inflammation and fibrosis transition primarily via the TLR3 core fucosylation-NF-κB signaling pathway.","method":"TEC-specific FUT8 conditional knockout mouse; IRI model; TLR3-NF-κB pathway analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional cell-type-specific KO with defined pathway readout, single lab","pmids":["37432656"],"is_preprint":false},{"year":2021,"finding":"FUT8 modifies core fucosylation of TNF receptors (TNFRs) in osteosarcoma; lower fucosylation of TNFRs activates the non-canonical NF-κB signaling pathway, decreasing mitochondria-dependent apoptosis in OS cells.","method":"FUT8 gain/loss-of-function; TNF receptor core fucosylation assay; NF-κB pathway analysis; apoptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — core fucosylation of defined substrate (TNFR) linked to downstream signaling, single lab","pmids":["34857735"],"is_preprint":false},{"year":2020,"finding":"FUT8-mediated core fucosylation of EGFR in cancer-associated fibroblasts (CAFs) promotes their cancer-promoting capacity in NSCLC; FUT8 overexpression in CAFs promotes invasive TME formation in vitro and in vivo via EGFR signaling regulation.","method":"3D-printed co-culture device; in vivo CAF/NSCLC co-injection; EGFR signaling analysis; FUT8 overexpression/KD","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo co-culture experiments with defined molecular target (EGFR CF), single lab","pmids":["32266093"],"is_preprint":false},{"year":2025,"finding":"FUT8-mediated core fucosylation of platelet adhesion receptors GPVI and integrin αIIbβ3 enhances their affinity/binding to type I collagen and fibrinogen respectively, leading to greater platelet activation and downstream signaling. Platelet-specific Fut8 deletion in two murine thrombosis models inhibits platelet activation and thrombus formation; FDW028 FUT8 inhibitor reduces platelet aggregation and protects mice from lethal thrombosis.","method":"Glycomics/glycoproteomics; binding affinity assay; platelet aggregometry; phospho-specific antibody signaling; murine thrombosis models; platelet-specific conditional KO; pharmacological FUT8 inhibition","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — defined glycoprotein substrates, binding assays, two in vivo models, genetic and pharmacological evidence in a single rigorous study","pmids":["42237907"],"is_preprint":false},{"year":2025,"finding":"FUT8 core fucosylation of GLUT1 at Asn45 (N45) increases GLUT1 protein half-life, enhancing glucose uptake and glycolytic flux (increased ECAR, ATP, lactate production) in HDM-stimulated bronchial epithelial cells; this drives EMT and release of IL-25 and IL-33. GLUT1 N45Q mutant (cannot be core-fucosylated) fails to rescue phenotype after FUT8 KD.","method":"FUT8 KD/OE; lectin pull-down; GLUT1 site-specific mutant (N45Q); ECAR measurement; IL-25/IL-33 ELISA; GLUT1 half-life assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-specific glycosite mutant, lectin pull-down, multiple functional readouts, single lab","pmids":["41027183"],"is_preprint":false},{"year":2021,"finding":"Quantitative glycoproteomics identified 140 common core-fucosylated target glycoproteins of FUT8 in highly invasive breast cancer cells. Among novel targets, core fucosylation of integrin αvβ5 is crucial for cell adhesion to vitronectin, and core fucosylation of IL6ST supports enhanced IL-6 and oncostatin M signaling relevant to breast cancer EMT and metastasis.","method":"Quantitative glycoproteomics (FUT8-KO vs WT); LCA blotting; LC-MS/MS validation; integrin adhesion assay","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mass spectrometry-based glycoproteomic target identification with biochemical and functional validation, single lab","pmids":["35303925"],"is_preprint":false},{"year":2026,"finding":"FUT8, via its fucosyltransferase activity, mediates core fucosylation of aminopeptidase N (APN) at specific N-glycosylation sites (pAPN N736, canine APN N747, feline APN N740), which is required for binding of alphacoronavirus spike proteins to APN and viral entry. pAPN lacking FUT8-mediated modification shows no binding to TGEV RBD.","method":"FUT8 KO cells; viral entry assay; APN glycoproteomic analysis; TGEV RBD binding assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific glycosite identification by glycoproteomics, KO functional validation for viral entry, conserved across multiple APN species","pmids":["42149951"],"is_preprint":false},{"year":2025,"finding":"FUT8 regulates macrophage migration in atherosclerosis by mediating α-1,6 fucosylation of the guidance receptor Unc5b (primarily in the ER); hypofucosylation of Unc5b promotes macrophage emigration and delays atherosclerotic progression via activation of the CDC42/PAK pathway. Conversely, Fut8-mediated hyperfucosylation of Unc5b inactivates CDC42/PAK and reduces migration, promoting atherosclerosis via ferroptosis (P53/SLC7A11/GPX4 pathway).","method":"IP assay for Fut8-Unc5b interaction; Unc5b fucosylation site mutants; ApoE-/- mouse model; siRNA/OE of Unc5b; wound healing; CDC42/PAK pathway analysis; ferroptosis assay","journal":"Cell & bioscience / Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP identifies FUT8-Unc5b interaction, glycosite mutants, in vivo mouse model with mechanistic pathway readout, two related papers","pmids":["36670464","40262667"],"is_preprint":false},{"year":2024,"finding":"FUT8 deficiency in cerebellar granule neuron progenitors impairs their proliferation and differentiation, compromises neuronal development, synaptic physiology and motor coordination. Mechanistically, Fut8 deficiency reduces Contactin 2 (Cntn2/neural cell adhesion molecule) expression; ectopic Cntn2 rescues the neuronal defects caused by Fut8 deficiency.","method":"Conditional cerebellar GNP-specific Fut8 KO; proliferation/differentiation assays; synaptic physiology; motor coordination test; Cntn2 expression rescue","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with rescue experiment, specific molecular target (Cntn2) identified, single lab","pmids":["39604780"],"is_preprint":false},{"year":2019,"finding":"HCV-induced FUT8 promotes proliferation of Huh7.5.1 cells by activating PI3K-AKT-NF-κB signaling and stimulates expression of drug-resistant proteins P-glycoprotein (P-gp) and MRP1, enhancing 5-FU chemoresistance. FUT8 silencing reduces proliferation and restores 5-FU sensitivity.","method":"FUT8 siRNA knockdown; PI3K-AKT-NF-κB pathway analysis; P-gp/MRP1 western blot; 5-FU cytotoxicity/LDH assay; flow cytometry","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined pathway and drug resistance readout, single lab","pmids":["31022917"],"is_preprint":false},{"year":2022,"finding":"The transcription factor LEF1 directly regulates FUT8 transcription; the lncRNA LEF1-AS1 recruits MLL1 to the LEF1 promoter, inducing H3K4me3 methylation and LEF1 expression, which in turn activates FUT8 transcription via the Wnt/β-catenin pathway. FUT8 overexpression rescues the suppressive effects of LEF1-AS1 knockdown on colorectal cancer cell malignancy.","method":"ChIP; RIP; EMSA; luciferase reporter assay; rescue OE experiment","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct LEF1-FUT8 promoter interaction demonstrated by ChIP/EMSA/luciferase, functional rescue, single lab","pmids":["34021424"],"is_preprint":false},{"year":2020,"finding":"Caveolin-1 promotes FUT8 expression by activating Wnt/β-catenin signaling, leading to downstream TCF/LEF binding to the FUT8 promoter and transcriptional activation. Cav-1 OE in low-Fut8 HCC cells induces Wnt/β-catenin activation and Fut8 upregulation; Cav-1 KD in high-Fut8 cells suppresses this.","method":"Cav-1 OE/KD; Wnt/β-catenin pathway analysis; TCF/LEF binding to FUT8 promoter; western blot","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined transcriptional mechanism with promoter binding evidence, OE/KD experiments, single lab","pmids":["32710651"],"is_preprint":false},{"year":2025,"finding":"FUT8 ablation in granulosa cells reduces cAMP production following FSH stimulation (reduced FSHR signaling), and decreases expression of FIGLA and embryonic development genes. Fut8-/- mouse oocytes exhibit abnormal zona pellucida formation and impaired embryonic development.","method":"FUT8-KD human granulosa cells (KGN-KD); Fut8-/- mouse ovary; cAMP assay after FSH; FIGLA/zona pellucida gene expression; embryo development assay","journal":"Journal of assisted reproduction and genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD cell model plus KO mouse with specific signaling (cAMP/FSHR) and developmental readouts, single lab","pmids":["40473957"],"is_preprint":false}],"current_model":"FUT8 is the sole mammalian α-1,6-fucosyltransferase that catalyzes transfer of fucose from GDP-β-L-fucose to the innermost GlcNAc of N-glycans (core fucosylation) via a GT-B fold catalytic mechanism; its SH3 domain controls enzymatic activity, Golgi/cell-surface localization, and interaction with the oligosaccharyltransferase subunit RPN1 (which stimulates FUT8 activity), while its α-helical stem region drives homodimerization and protein stability. Core fucosylation by FUT8 regulates the function, signaling capacity, stability, or trafficking of numerous glycoprotein targets including growth factor receptors (EGFR, TGF-βR, IGF-1R, VEGFR-2), immune checkpoint molecules (B7H3, PD-1/PD-L1), platelet adhesion receptors (GPVI, αIIbβ3), the ciliary transition zone protein TMEM67, LRP-1, mucins, and others, thereby controlling diverse processes ranging from cell signaling, migration, and immune evasion to ciliogenesis, platelet activation, and viral entry."},"narrative":{"mechanistic_narrative":"FUT8 is the sole mammalian α-1,6-fucosyltransferase, transferring fucose from GDP-β-L-fucose to the innermost GlcNAc of N-glycans (core fucosylation) and thereby tuning the signaling, stability, and trafficking of a broad set of glycoprotein targets [PMID:15352059, PMID:27008861]. Structurally it comprises an N-terminal α-helical (coiled-coil) domain, a GT-B fold catalytic domain that binds the GDP-fucose donor through a Rossmann fold, and a C-terminal SH3 domain, and it operates by a rapid-equilibrium random mechanism with induced-fit donor binding that preferentially modifies G0 biantennary complex N-glycans [PMID:17172260, PMID:16344263, PMID:33004438, PMID:35662980]. The SH3 domain (His-535) is itself required for catalysis and for Golgi/cell-surface trafficking and mediates a stimulatory interaction with the oligosaccharyltransferase subunit RPN1, while the α-helical stem region drives homodimerization/multimerization and protein stability [PMID:32350116, PMID:32147455, PMID:36336076]. Through core fucosylation FUT8 governs growth factor and cytokine receptor signaling—including TGF-β, activin, EGFR, IGF-1R, VEGFR-2, and TNF receptors—with consequences for receptor activation, dimerization, trafficking, and downstream MAPK/PI3K-AKT/NF-κB output, and loss of Fut8 in mice produces emphysema-like lung destruction via TGF-β and VEGFR-2 dysregulation [PMID:17132494, PMID:19179362, PMID:23796784, PMID:32888953, PMID:30712666, PMID:34857735]. FUT8 stabilizes or traffics numerous substrates by core fucosylation, including the immune checkpoint B7H3 (whose defucosylation triggers HSC70-mediated chaperone-mediated autophagy degradation), the ciliary transition-zone protein TMEM67, GLUT1, mucins, and the alphacoronavirus entry receptor aminopeptidase N, and core fucosylation of platelet receptors GPVI and integrin αIIbβ3 promotes platelet activation and thrombosis [PMID:32888953, PMID:33976130, PMID:36252012, PMID:37537172, PMID:40728580, PMID:42237907, PMID:41027183, PMID:42149951]. These activities place FUT8 as a driver of cancer invasion and metastasis, immune evasion, ciliogenesis, and reproductive and neuronal development, and its enzymatic mechanism has been exploited by GDP-dependent mechanism-based small-molecule inhibitors [PMID:28982386, PMID:28609658, PMID:39340265, PMID:42237907, PMID:40473957].","teleology":[{"year":2004,"claim":"Establishing FUT8 as the enzyme catalyzing core α-1,6-fucosylation defined its molecular activity and revealed that this modification governs antibody effector function.","evidence":"Sequential biallelic FUT8 knockout in CHO cells with ADCC and FcγRIIIa binding assays","pmids":["15352059"],"confidence":"High","gaps":["Did not resolve enzyme structure or catalytic residues","Scope of native glycoprotein substrates not defined"]},{"year":2005,"claim":"Kinetic and structural characterization of donor binding clarified how FUT8 recognizes GDP-fucose and which residues drive catalysis.","evidence":"Recombinant human FUT8 kinetics, GDP-fucose analogue inhibition, and X-ray crystallography revealing coiled-coil, GT-B/Rossmann catalytic, and SH3 domains","pmids":["16344263","17172260"],"confidence":"High","gaps":["Acceptor N-glycan binding mode not yet resolved","Functional role of the SH3 domain not addressed"]},{"year":2006,"claim":"Fut8 knockout mice connected core fucosylation to receptor signaling in vivo, showing that loss of fucosylation dysregulates TGF-β, EGF, PDGF, and LRP-1-dependent processes.","evidence":"Fut8-null mouse models with ligand rescue, gene reintroduction, endocytosis assay, and serum IGFBP-3 measurement","pmids":["17132494","16567404"],"confidence":"High","gaps":["Whether fucosylation acts directly on each receptor versus secondary effects not fully separated","Site-specific glycan determinants not mapped"]},{"year":2009,"claim":"Linking Fut8 loss to reduced VEGFR-2 and elevated ceramide-driven apoptosis extended the emphysema phenotype to a defined survival-receptor axis.","evidence":"Fut8 knockout mouse and siRNA in A549/TGP49 cells with TUNEL and ceramide measurements","pmids":["19179362"],"confidence":"Medium","gaps":["Mechanism coupling fucosylation loss to VEGFR-2 transcription unclear","Single-lab findings"]},{"year":2013,"claim":"FUT8 was shown to exert opposing, context-dependent effects on TGF-β-superfamily signaling and to control lineage outputs such as neuritogenesis and erythroid differentiation.","evidence":"siRNA/shRNA knockdown, overexpression, domain/loop mutagenesis, and rescue in PC12, MEL, and K562 cells","pmids":["23796784","23609441"],"confidence":"Medium","gaps":["Molecular basis of positive versus negative signaling outcomes not unified","Single-lab observations"]},{"year":2016,"claim":"Demonstrating GnT-I-independent fucosylation of high-mannose glycans broadened FUT8's substrate range beyond complex-type N-glycans.","evidence":"Stable FUT8 knockdown/overexpression in HEK293S GnT-I-/- cells with glycan mass spectrometry of EPO","pmids":["27008861"],"confidence":"High","gaps":["Physiological relevance of high-mannose core fucosylation not defined","Single rigorous study"]},{"year":2017,"claim":"Glycoproteomic and functional studies established FUT8 as a driver of cancer invasion and metastasis acting through specific substrates such as TGF-β receptors and L1CAM.","evidence":"shRNA/CRISPR loss-of-function, lentiviral gain-of-function, ligand binding assays, glycoproteomics, and in vivo metastasis/dissemination models in breast cancer and melanoma","pmids":["28982386","28609658"],"confidence":"High","gaps":["Full repertoire of metastasis-relevant substrates incomplete","Quantitative contribution of each target not ranked"]},{"year":2020,"claim":"Domain dissection revealed that the SH3 domain (His-535) is required for catalysis and trafficking and recruits RPN1 to stimulate activity, while α-helical domains drive the active homodimer.","evidence":"Truncation/site-directed mutagenesis, in vivo cross-linking, cell-surface biotinylation, proteomics, and RPN1 knockdown","pmids":["32350116","32147455"],"confidence":"High","gaps":["Structural model of the SH3/α-helical intermolecular interface not solved","Mechanism of RPN1 stimulation at atomic level unknown"]},{"year":2020,"claim":"Multiple ligand-bound crystal structures and acceptor specificity assays defined induced-fit donor binding and preference for the G0 biantennary glycan, refining substrate recognition rules.","evidence":"X-ray crystallography of FUT8 with GDP and four glycan acceptors plus active-site mutagenesis and kinetic analysis","pmids":["33004438"],"confidence":"High","gaps":["Conformational dynamics in the membrane-anchored enzyme not captured","Acceptor recognition for non-canonical substrates incomplete"]},{"year":2020,"claim":"FUT8-EGFR core fucosylation was shown to control EGFR dimerization, trafficking, and downstream signaling across prostate cancer, keratinocytes, and tumor-associated fibroblasts.","evidence":"Overexpression/knockdown, EGFR surface and dimerization assays, trafficking assays, conditional KO psoriasis mouse, and CAF co-culture models","pmids":["32085441","32888953","32266093"],"confidence":"High","gaps":["Site-specific EGFR glycan determinants not fully mapped","Whether effects generalize across tissues at endogenous levels untested"]},{"year":2021,"claim":"Substrate-stabilization mechanisms were defined, showing FUT8 core fucosylation protects target glycoproteins (B7H3, IGF-1R, mucins, TNFRs) from degradation or mislocalization, broadening its roles in immunosuppression, mucus biology, and apoptosis control.","evidence":"Knockdown/overexpression, protein stability and trafficking assays, immune functional assays, Fut8-/- mouse colon analysis, and in vivo therapy combination","pmids":["33976130","30712666","36252012","34857735"],"confidence":"High","gaps":["Direct versus indirect stabilization not always separated","Glycosite-resolved mechanisms incomplete for some targets"]},{"year":2021,"claim":"STD NMR and glycopeptide assays refined the rules of FUT8 substrate selection, showing it reads both glycan structure and the underlying peptide and requires prior GDP binding for optimal acceptor recognition.","evidence":"STD NMR, in vitro assays with N-glycopeptide libraries, and CHO glycoengineering with glycoproteomics","pmids":["35662980"],"confidence":"High","gaps":["Quantitative prediction of in vivo fucosylation site preference not established"]},{"year":2022,"claim":"Glycoproteomics expanded the FUT8 target catalogue and identified adhesion and cytokine-signaling substrates (integrin αvβ5, IL6ST) supporting metastatic phenotypes.","evidence":"Quantitative glycoproteomics of FUT8-KO versus WT breast cancer cells with LCA blotting, LC-MS/MS, and adhesion assays","pmids":["35303925"],"confidence":"Medium","gaps":["Functional validation limited to a subset of 140 targets","Single-lab dataset"]},{"year":2022,"claim":"Transcriptional control of FUT8 was defined, placing it downstream of Wnt/β-catenin-TCF/LEF, Caveolin-1, c-Myc/c-Myb, and p53 in disease contexts.","evidence":"ChIP, RIP, EMSA, luciferase reporters, and overexpression/knockdown rescue in colorectal, hepatocellular, and microglial models","pmids":["34021424","32710651","36692036"],"confidence":"Medium","gaps":["Relative weight of these regulators across tissues unknown","Single-lab mechanisms"]},{"year":2023,"claim":"Mechanistic studies tied FUT8 to degradation pathways and fibrosis signaling, showing defucosylation triggers chaperone-mediated autophagy of B7H3 and that FUT8-galectin-3 and FUT8-TLR3 axes drive fibrotic and inflammatory responses.","evidence":"Glycosite mutants, HSC70/LAMP2A co-IP, CMA assays, FUT8-Gal-3 co-IP, conditional FUT8 KO, and in vivo CRC, lung fibrosis, and renal IRI models","pmids":["37537172","36073215","37432656"],"confidence":"High","gaps":["Generality of CMA-coupled degradation to other substrates untested","Direct versus indirect interactions for Gal-3 axis not fully resolved"]},{"year":2024,"claim":"FUT8 was established as a trafficking and stabilization factor for diverse glycoproteins—TMEM67 in cilia, SEMA7A, CD36, GLUT1, and Cntn2—linking core fucosylation to ciliogenesis, metabolism, apoptosis, and neuronal development.","evidence":"Co-IP, glycosite-specific mutants, autophagy/half-life assays, conditional and global Fut8 KO mice, and rescue experiments across cilia, neuron, kidney, and epithelial systems","pmids":["40728580","38548747","39563263","41027183","39604780"],"confidence":"Medium","gaps":["Tissue-specific dominance among many substrates unclear","Several findings from single labs"]},{"year":2024,"claim":"Mechanism-based small-molecule FUT8 inhibitors that bind only in the presence of GDP were developed, validating the catalytic mechanism and enabling cellular suppression of core fucosylation.","evidence":"High-throughput screening, SPR, mechanistic covalent-inhibition studies, and cell-based EGFR/T-cell signaling assays","pmids":["39340265"],"confidence":"Medium","gaps":["In vivo selectivity and pharmacology not fully characterized in this study"]},{"year":2025,"claim":"Genetic and pharmacological evidence established FUT8 as a regulator of platelet receptor function, thrombosis, viral entry, atherosclerosis, and reproduction, identifying defined substrates including GPVI, αIIbβ3, aminopeptidase N, and Unc5b.","evidence":"Glycoproteomics, binding/aggregometry assays, glycosite mutants, platelet-specific and global Fut8 KO mice, FDW028 inhibitor, viral entry assays, and ApoE-/- and ovary models","pmids":["42237907","42149951","36670464","40262667","40473957"],"confidence":"High","gaps":["Therapeutic window for FUT8 inhibition across these systems undefined","Cross-species conservation of substrate sites incompletely mapped"]},{"year":null,"claim":"How FUT8 selects among its many substrates in a given cell type, and how its domain-mediated localization, dimerization, and RPN1 coupling are integrated to set fucosylation output in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking substrate-selection rules to in vivo glycoproteome","Atomic structure of the catalytically competent dimer/RPN1 complex lacking","Quantitative ranking of physiologically dominant substrates per tissue unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,9,14,18]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[16,17,23,27,32]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[21,36]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,9,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,16,20,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,23]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,35,38]}],"complexes":[],"partners":["RPN1","TMEM67","HSPA8","LGALS3","SEMA7A","UNC5B","EGFR","B7H3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYC5","full_name":"Alpha-(1,6)-fucosyltransferase","aliases":["Fucosyltransferase 8","GDP-L-Fuc:N-acetyl-beta-D-glucosaminide alpha1,6-fucosyltransferase","GDP-fucose--glycoprotein fucosyltransferase","Glycoprotein 6-alpha-L-fucosyltransferase"],"length_aa":575,"mass_kda":66.5,"function":"Catalyzes the addition of fucose in alpha 1-6 linkage to the first GlcNAc residue, next to the peptide chains in N-glycans (PubMed:17172260, PubMed:29304374, PubMed:36280670, PubMed:9133635). Fucosylates the reducing GlcNAc residue in complex-type N-glycans attached on the fragment crystallizable (Fc) of IgGs. Fully converts Fc glycoforms containing one or two terminal GlcNAc moieties (G0-GlcNAc and G0) (PubMed:36280670)","subcellular_location":"Golgi apparatus, Golgi stack membrane","url":"https://www.uniprot.org/uniprotkb/Q9BYC5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FUT8","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FUT8","total_profiled":1310},"omim":[{"mim_id":"618005","title":"CONGENITAL DISORDER OF GLYCOSYLATION WITH DEFECTIVE FUCOSYLATION 1; CDGF1","url":"https://www.omim.org/entry/618005"},{"mim_id":"602589","title":"FUCOSYLTRANSFERASE 8; FUT8","url":"https://www.omim.org/entry/602589"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FUT8"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9BYC5","domains":[{"cath_id":"1.10.287.1060","chopping":"111-174","consensus_level":"high","plddt":97.7145,"start":111,"end":174},{"cath_id":"-","chopping":"185-315","consensus_level":"high","plddt":97.8408,"start":185,"end":315},{"cath_id":"3.40.50.11350","chopping":"338-491","consensus_level":"high","plddt":95.3438,"start":338,"end":491},{"cath_id":"2.30.30.40","chopping":"505-564","consensus_level":"high","plddt":98.3245,"start":505,"end":564}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYC5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYC5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYC5-F1-predicted_aligned_error_v6.png","plddt_mean":92.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FUT8","jax_strain_url":"https://www.jax.org/strain/search?query=FUT8"},"sequence":{"accession":"Q9BYC5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYC5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYC5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYC5"}},"corpus_meta":[{"pmid":"15352059","id":"PMC_15352059","title":"Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity.","date":"2004","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/15352059","citation_count":432,"is_preprint":false},{"pmid":"28609658","id":"PMC_28609658","title":"A Systems Biology Approach Identifies FUT8 as a Driver of Melanoma Metastasis.","date":"2017","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/28609658","citation_count":248,"is_preprint":false},{"pmid":"28982386","id":"PMC_28982386","title":"FUT8 promotes breast cancer cell invasiveness by remodeling TGF-β receptor core fucosylation.","date":"2017","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/28982386","citation_count":181,"is_preprint":false},{"pmid":"33976130","id":"PMC_33976130","title":"FUT8-mediated aberrant N-glycosylation of B7H3 suppresses the immune response in triple-negative breast cancer.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33976130","citation_count":154,"is_preprint":false},{"pmid":"15515168","id":"PMC_15515168","title":"Engineering Chinese hamster ovary cells to maximize effector function of produced antibodies using FUT8 siRNA.","date":"2004","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/15515168","citation_count":123,"is_preprint":false},{"pmid":"17172260","id":"PMC_17172260","title":"Crystal structure of mammalian alpha1,6-fucosyltransferase, FUT8.","date":"2006","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/17172260","citation_count":117,"is_preprint":false},{"pmid":"18047682","id":"PMC_18047682","title":"Double knockdown of alpha1,6-fucosyltransferase (FUT8) and GDP-mannose 4,6-dehydratase (GMD) in antibody-producing cells: a new strategy for generating fully non-fucosylated therapeutic antibodies with enhanced ADCC.","date":"2007","source":"BMC biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/18047682","citation_count":114,"is_preprint":false},{"pmid":"20564614","id":"PMC_20564614","title":"Highly efficient deletion of FUT8 in CHO cell lines using zinc-finger nucleases yields cells that produce completely nonfucosylated antibodies.","date":"2010","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/20564614","citation_count":113,"is_preprint":false},{"pmid":"14568171","id":"PMC_14568171","title":"Expression of alpha1,6-fucosyltransferase (FUT8) in papillary carcinoma of the thyroid: its linkage to biological aggressiveness and anaplastic transformation.","date":"2003","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/14568171","citation_count":82,"is_preprint":false},{"pmid":"17132494","id":"PMC_17132494","title":"Phenotype changes of Fut8 knockout mouse: core fucosylation is crucial for the function of growth factor 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N-Glycans.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27008861","citation_count":55,"is_preprint":false},{"pmid":"37537172","id":"PMC_37537172","title":"FDW028, a novel FUT8 inhibitor, impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37537172","citation_count":50,"is_preprint":false},{"pmid":"32266093","id":"PMC_32266093","title":"α1,6-Fucosyltransferase (FUT8) regulates the cancer-promoting capacity of cancer-associated fibroblasts (CAFs) by modifying EGFR core fucosylation (CF) in non-small cell lung cancer (NSCLC).","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32266093","citation_count":48,"is_preprint":false},{"pmid":"35662980","id":"PMC_35662980","title":"FUT8-Directed Core Fucosylation of 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catalyzes transfer of fucose from GDP-fucose to the core N-acetylglucosamine of N-glycans via an α-1,6-linkage; knockout of both FUT8 alleles in CHO cells produces completely defucosylated antibodies with ~100-fold enhanced ADCC activity via stronger FcγRIIIa binding.\",\n      \"method\": \"Sequential homologous recombination knockout in CHO cells; ADCC assay; FcγRIIIa binding assay\",\n      \"journal\": \"Biotechnology and bioengineering\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct enzymatic knockout with defined biochemical and cellular readouts, replicated in multiple subsequent studies\",\n      \"pmids\": [\"15352059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of human FUT8 at 2.6 Å resolution reveals three domains: an N-terminal coiled-coil (α-helical) domain, a GT-B fold catalytic domain with a Rossmann fold for donor (GDP-fucose) binding, and a C-terminal SH3 domain. Conserved residues in three regions participate in the Rossmann fold and act as the donor binding site or in catalysis.\",\n      \"method\": \"X-ray crystallography at 2.6 Å resolution\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional domain identification, foundational structural paper\",\n      \"pmids\": [\"17172260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FUT8 catalyzes GDP-fucose transfer via a rapid equilibrium random mechanism. The enzyme strongly recognizes the base portion and diphosphoryl group of GDP-β-L-fucose; two conserved neighboring arginine residues play an important role in donor substrate binding.\",\n      \"method\": \"Recombinant human FUT8 produced in baculovirus-infected insect cells; kinetic analysis; inhibition studies with GDP-fucose derivatives\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with kinetic characterization and substrate analogue inhibition in a single rigorous study\",\n      \"pmids\": [\"16344263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Fut8 knockout mice, TGF-β1 receptor activation and signaling are markedly dysregulated, causing overexpression of MMPs (MMP12, MMP13) and downregulation of extracellular matrix proteins such as elastin, contributing to emphysema-like lung destruction. Therapeutic administration of exogenous TGF-β1 rescued the knockout mice from emphysema. Loss of core fucosylation on EGF and PDGF receptors also downregulates receptor-mediated signaling; reintroduction of Fut8 rescues these signaling impairments.\",\n      \"method\": \"Fut8 knockout mouse model; TGF-β1 rescue experiment; Fut8 gene reintroduction into null cells\",\n      \"journal\": \"Methods in enzymology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with phenotypic rescue by exogenous ligand and gene reintroduction, multiple receptors tested\",\n      \"pmids\": [\"17132494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Loss of core fucosylation in Fut8-null mouse cells impairs LRP-1-mediated endocytosis of IGFBP-3, leading to markedly elevated serum IGFBP-3 levels in Fut8-/- mice. Re-introduction of Fut8 restores LRP-1 endocytic activity.\",\n      \"method\": \"Fut8 knockout mouse model; endocytosis assay; Fut8 gene reintroduction; serum IGFBP-3 measurement\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with functional rescue, defined substrate (LRP-1), and in vivo serum measurement\",\n      \"pmids\": [\"16567404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fut8 is required for expression of VEGFR-2; loss of Fut8 in knockout mice suppresses VEGFR-2 mRNA and protein expression, increases ceramide levels (an apoptosis inducer), and increases TUNEL-positive septal cells, contributing to emphysema-like lung changes.\",\n      \"method\": \"Fut8 knockout mouse model; siRNA knockdown in A549 and TGP49 cells; TUNEL assay; ceramide measurement\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and siRNA with multiple readouts in a single lab\",\n      \"pmids\": [\"19179362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Donor substrate GDP-fucose binds FUT8 with guanine specifically recognized by His363 and Asp453, the pyrophosphate contributes major binding affinity, and Arg365 contacts both the β-phosphate and the fucose moiety simultaneously.\",\n      \"method\": \"STD NMR; surface plasmon resonance; molecular dynamics simulation; structural analogy with cePOFUT\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR epitope mapping and SPR from a single lab without mutagenesis validation of all identified contacts\",\n      \"pmids\": [\"22982178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of Fut8 in PC12 cells promotes neurite formation and induction of neurofilament expression by increasing phospho-Smad2 levels via enhanced activin receptor signaling. α-1,6-Fucosylation on activin receptors negatively regulates activin-mediated signaling (reduced fucosylation on activin receptors in KD cells without changing total receptor expression). Restoration of Fut8 expression rescues these changes, demonstrating Fut8 plays a dual opposing role in TGF-β/activin-mediated signaling.\",\n      \"method\": \"siRNA knockdown; Fut8 gene restoration; phospho-Smad2 western blot; neurite formation assay; activin receptor inhibition\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and rescue experiments with multiple orthogonal readouts in a single lab\",\n      \"pmids\": [\"23796784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FUT8 overexpression inhibits hemoglobin production during erythroid differentiation of murine erythroleukemia and K562 human cells. The donor substrate-binding domain and a flexible loop of FUT8 are essential for this inhibitory function. c-Myc and c-Myb positively regulate Fut8 expression; FUT8 shRNA induces hemoglobin production and increases transferrin receptor/glycophorin A-positive cells.\",\n      \"method\": \"Overexpression and shRNA knockdown; hemoglobin assay; domain/loop mutagenesis; flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain mutagenesis and KD/OE with specific cellular phenotype readout\",\n      \"pmids\": [\"23609441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FUT8 (mammalian α1,6-fucosyltransferase) is the sole enzyme responsible for GnT-I-independent core fucosylation of high-mannose N-glycans; in HEK293S GnT-I-/- cells, FUT8 knockdown abolishes core fucosylation of Man5GlcNAc2 glycoforms, whereas FUT8 overexpression produces fully core-fucosylated high-mannose glycoforms.\",\n      \"method\": \"Stable FUT8 knockdown and overexpression in HEK293S GnT-I-/- cells; glycan mass spectrometry analysis of EPO\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-like cell genetic system with mass spectrometry glycan verification in a single rigorous study\",\n      \"pmids\": [\"27008861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FUT8-mediated core fucosylation of TGF-β receptor complexes facilitates TGF-β binding and enhances downstream signaling in breast carcinoma cells, promoting EMT and invasion. FUT8 knockdown (shRNA or CRISPR) suppresses invasiveness of highly aggressive breast cancer cells and impairs lung metastasis in vivo.\",\n      \"method\": \"Lentivirus gain-of-function; shRNA/CRISPR loss-of-function; lectin blot; luciferase assay; in vitro ligand binding assay; transwell invasion; mammary fat pad xenograft\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical binding assay, functional KD/OE, in vivo model) with defined molecular target (TGF-β receptor)\",\n      \"pmids\": [\"28982386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FUT8 is a driver of melanoma metastasis; FUT8 silencing suppresses invasion and tumor dissemination. Glycoprotein targets of FUT8 are enriched in cell migration proteins including L1CAM; core fucosylation by FUT8 impacts L1CAM cleavage and L1CAM-supported invasion.\",\n      \"method\": \"In vitro invasion assay; in vivo tumor dissemination model; glycoproteomic identification of FUT8 targets; FUT8 silencing\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo functional studies in patient samples plus identification of molecular target with mechanistic follow-up\",\n      \"pmids\": [\"28609658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The SH3 domain of FUT8 is essential for enzymatic activity (both in cells and in vitro); His-535 in the SH3 domain is the critical residue for catalytic activity. The SH3 domain also controls FUT8 trafficking to the cell surface. FUT8 binds ribophorin I (RPN1), a subunit of the oligosaccharyltransferase complex, in an SH3-dependent manner; RPN1 knockdown decreases FUT8 activity and core fucose levels, indicating RPN1 stimulates FUT8 activity.\",\n      \"method\": \"Truncated FUT8 constructs; immunofluorescence; FACS; cell-surface biotinylation; proteomics; LC-ESI-MS; His-535 mutagenesis; RPN1 siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis, multiple orthogonal methods, identified interacting protein with functional validation, single rigorous study\",\n      \"pmids\": [\"32350116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The α-helical (N-terminal coiled-coil) and SH3 domains of FUT8 are both required for full enzymatic activity and form the basis of FUT8 homodimerization via intermolecular hydrophobic interactions of α-helical domains. In vivo cross-linking experiments show the SH3 domain is positioned in close proximity to the α-helical domain in an intermolecular manner, forming the active quaternary structure.\",\n      \"method\": \"Domain truncation; site-directed mutagenesis; in vivo disulfide cross-linking; heterologous expression in Sf21/COS-1 cells; SDS-PAGE enzymatic activity assay\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis and cross-linking in a single lab with multiple domain mutants\",\n      \"pmids\": [\"32147455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FUT8 crystal structures in complex with a donor substrate analog (GDP) and four distinct glycan acceptors reveal: active site loop ordering correlates with increased GDP occupancy (induced-fit binding); binding site complementarity and steric hindrance tune substrate affinity; the G0 biantennary complex N-glycan is preferred. FUT8 structure comparison with other fucosyltransferases identifies conserved and divergent GT-B fold features for donor/acceptor recognition.\",\n      \"method\": \"X-ray crystallography of multiple FUT8-ligand complexes; active site mutagenesis with kinetic analysis; glycan acceptor library specificity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with active site mutagenesis and kinetic validation in a single rigorous study\",\n      \"pmids\": [\"33004438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FUT8 overexpression in prostate cancer cells upregulates cell-surface EGFR and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions (castration resistance). Castration in xenograft models induces FUT8 overexpression associated with increased EGFR expression.\",\n      \"method\": \"Proteomic analysis; FUT8 overexpression; EGFR surface expression measurement; androgen deprivation in vitro and xenograft\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic approach with OE experiment and in vivo model, single lab\",\n      \"pmids\": [\"32085441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FUT8 core fucosylation of EGFR is required for EGFR overactivation in keratinocytes; FUT8 loss-of-function reduces EGFR/AKT signaling, reduces ligand-induced EGFR dimerization, slows EGF-EGFR complex trafficking to the perinuclear region, and ameliorates psoriasis-like phenotype in a conditional knockout mouse model.\",\n      \"method\": \"shFUT8; FUT8 gain-of-function; EGFR signaling by western blot; EGFR dimerization assay; trafficking assay; conditional FUT8 KO in IL-23 psoriasis mouse model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function, gain-of-function, in vivo conditional KO with mechanistic readouts including dimerization and trafficking, multiple orthogonal methods\",\n      \"pmids\": [\"32888953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FUT8 catalyzes core fucosylation of B7H3 (CD276) N-glycans in TNBC cells, which stabilizes B7H3 protein and maintains its high expression level, contributing to immunosuppression. FUT8 knockdown reduces glycosylated B7H3-mediated immunosuppressive function.\",\n      \"method\": \"FUT8 knockdown; glycoprotein stability assay; immune functional assay; combination with anti-PDL1 in B7H3-positive tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD experiments with defined substrate (B7H3), protein stability readout, functional immune assay, and in vivo combination therapy, single rigorous study\",\n      \"pmids\": [\"33976130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FUT8 substrate specificity is regulated by the glycan structure and protein/peptide environment. FUT8 recognizes all sugar units of the G0 N-glycan (shown by STD NMR) and most residues of the Asn-X-Thr sequon. Prior FUT8 binding to GDP is required for optimal N-glycan recognition. The underlying peptide influences fucosylation of paucimannose and high-mannose N-glycans but not complex-type N-glycans.\",\n      \"method\": \"STD NMR; in vitro FUT8 assay with N-glycopeptide library; CHO cell glycoengineering; glycoproteomic analysis\",\n      \"journal\": \"ACS catalysis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR, in vitro enzymatic assay, and cell-based glycoengineering in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"35662980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FUT8 overexpression increases delivery of MUC1 to the plasma membrane and extracellular release of MUC2 and MUC5AC. Mucins secreted by FUT8-overexpressing cells are more resistant to removal from the cell surface. FUT8 KD causes intracellular MUC1 accumulation and alters the MUC2:MUC5AC ratio. Fut8-/- mice show a thinner proximal colon mucus layer with altered neutral-to-acidic mucin ratio.\",\n      \"method\": \"FUT8 overexpression/KD in HT29-18N2 cells; mucin trafficking assay; Fut8-/- mouse colonic mucus analysis; mucin resistance assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-based gain/loss-of-function plus Fut8 KO mouse model with specific mechanistic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"36252012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FUT8 modifies α1,6-fucosylation of IGF-1 receptor (IGF-1R), regulates IGF-1-dependent activation of IGF-1R, and regulates downstream MAPK and PI3K/Akt signaling in trophoblastic cells. FUT8 knockdown suppresses proliferation, EMT, migration and invasion of JAR and JEG-3 cells.\",\n      \"method\": \"siRNA knockdown; immunoprecipitation; IGF-1R phosphorylation assay; functional cell assays\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP of core-fucosylated IGF-1R combined with functional KD and signaling readouts, single lab\",\n      \"pmids\": [\"30712666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The FUT8 stem region (two α-helices) is essential for FUT8 multimer (oligomer) formation but not for catalytic activity per se. Loss of the stem region destabilizes FUT8 protein, increases ER localization, and shortens its half-life. The first helix of the stem region is critical for multimer formation.\",\n      \"method\": \"FUT8 stem deletion mutants expressed in FUT8-KO HEK293 cells; immunoprecipitation; native-PAGE; subcellular localization by immunofluorescence; half-life measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis with multiple structural and functional readouts in a clean KO reconstitution system\",\n      \"pmids\": [\"36336076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FUT8-mediated core fucosylation is required for amyloid-β oligomer (AβO)-induced pro-inflammatory activation of human iPSC-derived microglia. FUT8/core fucosylation inhibition reduces pro-inflammatory cytokines, suppresses p38MAPK activation, and rectifies phagocytic deficits. p53 binds two consensus sites in the FUT8 promoter and p53 knockdown abolishes FUT8 overexpression in AβO-activated microglia, placing FUT8 downstream of p53 in microglial signaling.\",\n      \"method\": \"siRNA-mediated FUT8 KD in human iPSC-derived microglia; fucosylation inhibitor; cytokine assay; p38MAPK assay; phagocytosis assay; ChIP-like p53 promoter binding analysis; p53 siRNA\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and pharmacological inhibition with multiple functional readouts plus upstream regulator identification, single lab\",\n      \"pmids\": [\"36692036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FUT8 inhibition (by FUT8 silencing) causes defucosylation at N104 on B7-H3, which allows HSC70 (HSPA8) to bind the 106-110 SLRLQ motif of B7-H3 and drives lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy (CMA) pathway. A selective small-molecule FUT8 inhibitor FDW028 recapitulates this mechanism and prolongs survival in CRC pulmonary metastasis models.\",\n      \"method\": \"FUT8 silencing; site-specific glycan mutants (N104); HSC70/LAMP2A co-IP; CMA pathway assay; FDW028 inhibitor characterization; in vivo mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific glycosite mutant, protein interaction validated by IP, pathway mechanism with CMA readout, and pharmacological validation in vivo\",\n      \"pmids\": [\"37537172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FUT8 regulates TGF-β1-induced pulmonary fibroblast (MRC-5) proliferation, migration and fibrosis by interacting with galectin-3 (Gal-3), as demonstrated by co-immunoprecipitation. FUT8 silencing downregulates Gal-3 expression and inhibits FAK/Akt signaling; Gal-3 overexpression reverses the effects of FUT8 silencing.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; western blot; CCK-8; wound healing; bleomycin mouse model with sh-FUT8\",\n      \"journal\": \"Nan fang yi ke da xue xue bao\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying FUT8-Gal-3 interaction, functional rescue with Gal-3 OE, in vivo mouse model\",\n      \"pmids\": [\"36073215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FUT8 catalyzes core fucosylation of SEMA7A at N-linked glycosylation sites (Asn 105, 157, 258, 330, and 602) via direct protein-protein interaction. Core fucosylation is required for SEMA7A intracellular trafficking from cytoplasm to cytomembrane. EGF increases SEMA7A binding affinity to FUT8, enhancing fucosylation; TGF-β1 promotes SEMA7A glycosylation via EMT induction.\",\n      \"method\": \"Co-IP (FUT8-SEMA7A interaction); glycosite-specific mutants; subcellular trafficking assay; EGF/TGF-β1 treatment\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction by Co-IP, specific glycosite identification, trafficking functional assay, single lab\",\n      \"pmids\": [\"38548747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A selective FUT8 inhibitor with KD = 49 nM binds FUT8 only in the presence of GDP (product of the enzymatic reaction), generates a reactive naphthoquinone methide derivative at the active site that covalently reacts with FUT8 (mechanism-based inhibition). Prodrug derivatization enables cellular suppression of core fucose expression and subsequent EGFR and T-cell signaling.\",\n      \"method\": \"High-throughput screening; SPR binding assay; mechanistic inhibitor studies; cell-based EGFR and T-cell signaling assays\",\n      \"journal\": \"Angewandte Chemie (International ed. in English)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding characterization with mechanistic study plus cell-based validation in a single study\",\n      \"pmids\": [\"39340265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FUT8 interacts with TMEM67 (a ciliary transition zone component) and catalyzes its core fucosylation, which stabilizes TMEM67 by preventing its degradation via autophagy. Loss of core fucosylation of TMEM67 causes mislocalization from the transition zone. Fut8-deficient mice exhibit ciliary defects in kidney, brain, and trachea.\",\n      \"method\": \"Mass spectrometry proteomics; Co-IP (FUT8-TMEM67); core fucosylation assay; autophagy degradation assay; Fut8-deficient mouse ciliary phenotype analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct interaction by Co-IP, degradation mechanism established, in vivo KO mouse with specific ciliary phenotype, multiple organs analyzed\",\n      \"pmids\": [\"40728580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FUT8 upregulates CD36 expression and its core fucosylation level in pericytes, contributing to activation of the mitochondrial-dependent apoptosis signaling pathway and pericyte-myofibroblast transition in AKI-to-CKD progression.\",\n      \"method\": \"IP and confocal immunofluorescence for CD36 core fucosylation; IRI mouse model; H/R cell model; flow cytometry apoptosis; JC-1 mitochondrial membrane potential\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-based core fucosylation detection of CD36, in vivo and in vitro models with signaling readout, single lab\",\n      \"pmids\": [\"39563263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Renal tubular epithelial cell-specific deletion of FUT8 ameliorates IRI-induced renal interstitial inflammation and fibrosis transition primarily via the TLR3 core fucosylation-NF-κB signaling pathway.\",\n      \"method\": \"TEC-specific FUT8 conditional knockout mouse; IRI model; TLR3-NF-κB pathway analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional cell-type-specific KO with defined pathway readout, single lab\",\n      \"pmids\": [\"37432656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FUT8 modifies core fucosylation of TNF receptors (TNFRs) in osteosarcoma; lower fucosylation of TNFRs activates the non-canonical NF-κB signaling pathway, decreasing mitochondria-dependent apoptosis in OS cells.\",\n      \"method\": \"FUT8 gain/loss-of-function; TNF receptor core fucosylation assay; NF-κB pathway analysis; apoptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — core fucosylation of defined substrate (TNFR) linked to downstream signaling, single lab\",\n      \"pmids\": [\"34857735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FUT8-mediated core fucosylation of EGFR in cancer-associated fibroblasts (CAFs) promotes their cancer-promoting capacity in NSCLC; FUT8 overexpression in CAFs promotes invasive TME formation in vitro and in vivo via EGFR signaling regulation.\",\n      \"method\": \"3D-printed co-culture device; in vivo CAF/NSCLC co-injection; EGFR signaling analysis; FUT8 overexpression/KD\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo co-culture experiments with defined molecular target (EGFR CF), single lab\",\n      \"pmids\": [\"32266093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT8-mediated core fucosylation of platelet adhesion receptors GPVI and integrin αIIbβ3 enhances their affinity/binding to type I collagen and fibrinogen respectively, leading to greater platelet activation and downstream signaling. Platelet-specific Fut8 deletion in two murine thrombosis models inhibits platelet activation and thrombus formation; FDW028 FUT8 inhibitor reduces platelet aggregation and protects mice from lethal thrombosis.\",\n      \"method\": \"Glycomics/glycoproteomics; binding affinity assay; platelet aggregometry; phospho-specific antibody signaling; murine thrombosis models; platelet-specific conditional KO; pharmacological FUT8 inhibition\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — defined glycoprotein substrates, binding assays, two in vivo models, genetic and pharmacological evidence in a single rigorous study\",\n      \"pmids\": [\"42237907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT8 core fucosylation of GLUT1 at Asn45 (N45) increases GLUT1 protein half-life, enhancing glucose uptake and glycolytic flux (increased ECAR, ATP, lactate production) in HDM-stimulated bronchial epithelial cells; this drives EMT and release of IL-25 and IL-33. GLUT1 N45Q mutant (cannot be core-fucosylated) fails to rescue phenotype after FUT8 KD.\",\n      \"method\": \"FUT8 KD/OE; lectin pull-down; GLUT1 site-specific mutant (N45Q); ECAR measurement; IL-25/IL-33 ELISA; GLUT1 half-life assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-specific glycosite mutant, lectin pull-down, multiple functional readouts, single lab\",\n      \"pmids\": [\"41027183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Quantitative glycoproteomics identified 140 common core-fucosylated target glycoproteins of FUT8 in highly invasive breast cancer cells. Among novel targets, core fucosylation of integrin αvβ5 is crucial for cell adhesion to vitronectin, and core fucosylation of IL6ST supports enhanced IL-6 and oncostatin M signaling relevant to breast cancer EMT and metastasis.\",\n      \"method\": \"Quantitative glycoproteomics (FUT8-KO vs WT); LCA blotting; LC-MS/MS validation; integrin adhesion assay\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mass spectrometry-based glycoproteomic target identification with biochemical and functional validation, single lab\",\n      \"pmids\": [\"35303925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FUT8, via its fucosyltransferase activity, mediates core fucosylation of aminopeptidase N (APN) at specific N-glycosylation sites (pAPN N736, canine APN N747, feline APN N740), which is required for binding of alphacoronavirus spike proteins to APN and viral entry. pAPN lacking FUT8-mediated modification shows no binding to TGEV RBD.\",\n      \"method\": \"FUT8 KO cells; viral entry assay; APN glycoproteomic analysis; TGEV RBD binding assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific glycosite identification by glycoproteomics, KO functional validation for viral entry, conserved across multiple APN species\",\n      \"pmids\": [\"42149951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT8 regulates macrophage migration in atherosclerosis by mediating α-1,6 fucosylation of the guidance receptor Unc5b (primarily in the ER); hypofucosylation of Unc5b promotes macrophage emigration and delays atherosclerotic progression via activation of the CDC42/PAK pathway. Conversely, Fut8-mediated hyperfucosylation of Unc5b inactivates CDC42/PAK and reduces migration, promoting atherosclerosis via ferroptosis (P53/SLC7A11/GPX4 pathway).\",\n      \"method\": \"IP assay for Fut8-Unc5b interaction; Unc5b fucosylation site mutants; ApoE-/- mouse model; siRNA/OE of Unc5b; wound healing; CDC42/PAK pathway analysis; ferroptosis assay\",\n      \"journal\": \"Cell & bioscience / Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP identifies FUT8-Unc5b interaction, glycosite mutants, in vivo mouse model with mechanistic pathway readout, two related papers\",\n      \"pmids\": [\"36670464\", \"40262667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FUT8 deficiency in cerebellar granule neuron progenitors impairs their proliferation and differentiation, compromises neuronal development, synaptic physiology and motor coordination. Mechanistically, Fut8 deficiency reduces Contactin 2 (Cntn2/neural cell adhesion molecule) expression; ectopic Cntn2 rescues the neuronal defects caused by Fut8 deficiency.\",\n      \"method\": \"Conditional cerebellar GNP-specific Fut8 KO; proliferation/differentiation assays; synaptic physiology; motor coordination test; Cntn2 expression rescue\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with rescue experiment, specific molecular target (Cntn2) identified, single lab\",\n      \"pmids\": [\"39604780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HCV-induced FUT8 promotes proliferation of Huh7.5.1 cells by activating PI3K-AKT-NF-κB signaling and stimulates expression of drug-resistant proteins P-glycoprotein (P-gp) and MRP1, enhancing 5-FU chemoresistance. FUT8 silencing reduces proliferation and restores 5-FU sensitivity.\",\n      \"method\": \"FUT8 siRNA knockdown; PI3K-AKT-NF-κB pathway analysis; P-gp/MRP1 western blot; 5-FU cytotoxicity/LDH assay; flow cytometry\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined pathway and drug resistance readout, single lab\",\n      \"pmids\": [\"31022917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor LEF1 directly regulates FUT8 transcription; the lncRNA LEF1-AS1 recruits MLL1 to the LEF1 promoter, inducing H3K4me3 methylation and LEF1 expression, which in turn activates FUT8 transcription via the Wnt/β-catenin pathway. FUT8 overexpression rescues the suppressive effects of LEF1-AS1 knockdown on colorectal cancer cell malignancy.\",\n      \"method\": \"ChIP; RIP; EMSA; luciferase reporter assay; rescue OE experiment\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct LEF1-FUT8 promoter interaction demonstrated by ChIP/EMSA/luciferase, functional rescue, single lab\",\n      \"pmids\": [\"34021424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Caveolin-1 promotes FUT8 expression by activating Wnt/β-catenin signaling, leading to downstream TCF/LEF binding to the FUT8 promoter and transcriptional activation. Cav-1 OE in low-Fut8 HCC cells induces Wnt/β-catenin activation and Fut8 upregulation; Cav-1 KD in high-Fut8 cells suppresses this.\",\n      \"method\": \"Cav-1 OE/KD; Wnt/β-catenin pathway analysis; TCF/LEF binding to FUT8 promoter; western blot\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined transcriptional mechanism with promoter binding evidence, OE/KD experiments, single lab\",\n      \"pmids\": [\"32710651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT8 ablation in granulosa cells reduces cAMP production following FSH stimulation (reduced FSHR signaling), and decreases expression of FIGLA and embryonic development genes. Fut8-/- mouse oocytes exhibit abnormal zona pellucida formation and impaired embryonic development.\",\n      \"method\": \"FUT8-KD human granulosa cells (KGN-KD); Fut8-/- mouse ovary; cAMP assay after FSH; FIGLA/zona pellucida gene expression; embryo development assay\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD cell model plus KO mouse with specific signaling (cAMP/FSHR) and developmental readouts, single lab\",\n      \"pmids\": [\"40473957\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FUT8 is the sole mammalian α-1,6-fucosyltransferase that catalyzes transfer of fucose from GDP-β-L-fucose to the innermost GlcNAc of N-glycans (core fucosylation) via a GT-B fold catalytic mechanism; its SH3 domain controls enzymatic activity, Golgi/cell-surface localization, and interaction with the oligosaccharyltransferase subunit RPN1 (which stimulates FUT8 activity), while its α-helical stem region drives homodimerization and protein stability. Core fucosylation by FUT8 regulates the function, signaling capacity, stability, or trafficking of numerous glycoprotein targets including growth factor receptors (EGFR, TGF-βR, IGF-1R, VEGFR-2), immune checkpoint molecules (B7H3, PD-1/PD-L1), platelet adhesion receptors (GPVI, αIIbβ3), the ciliary transition zone protein TMEM67, LRP-1, mucins, and others, thereby controlling diverse processes ranging from cell signaling, migration, and immune evasion to ciliogenesis, platelet activation, and viral entry.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FUT8 is the sole mammalian α-1,6-fucosyltransferase, transferring fucose from GDP-β-L-fucose to the innermost GlcNAc of N-glycans (core fucosylation) and thereby tuning the signaling, stability, and trafficking of a broad set of glycoprotein targets [#0, #9]. Structurally it comprises an N-terminal α-helical (coiled-coil) domain, a GT-B fold catalytic domain that binds the GDP-fucose donor through a Rossmann fold, and a C-terminal SH3 domain, and it operates by a rapid-equilibrium random mechanism with induced-fit donor binding that preferentially modifies G0 biantennary complex N-glycans [#1, #2, #14, #18]. The SH3 domain (His-535) is itself required for catalysis and for Golgi/cell-surface trafficking and mediates a stimulatory interaction with the oligosaccharyltransferase subunit RPN1, while the α-helical stem region drives homodimerization/multimerization and protein stability [#12, #13, #21]. Through core fucosylation FUT8 governs growth factor and cytokine receptor signaling—including TGF-β, activin, EGFR, IGF-1R, VEGFR-2, and TNF receptors—with consequences for receptor activation, dimerization, trafficking, and downstream MAPK/PI3K-AKT/NF-κB output, and loss of Fut8 in mice produces emphysema-like lung destruction via TGF-β and VEGFR-2 dysregulation [#3, #5, #7, #16, #20, #30]. FUT8 stabilizes or traffics numerous substrates by core fucosylation, including the immune checkpoint B7H3 (whose defucosylation triggers HSC70-mediated chaperone-mediated autophagy degradation), the ciliary transition-zone protein TMEM67, GLUT1, mucins, and the alphacoronavirus entry receptor aminopeptidase N, and core fucosylation of platelet receptors GPVI and integrin αIIbβ3 promotes platelet activation and thrombosis [#16, #17, #19, #23, #27, #32, #33, #35]. These activities place FUT8 as a driver of cancer invasion and metastasis, immune evasion, ciliogenesis, and reproductive and neuronal development, and its enzymatic mechanism has been exploited by GDP-dependent mechanism-based small-molecule inhibitors [#10, #11, #26, #32, #41].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing FUT8 as the enzyme catalyzing core α-1,6-fucosylation defined its molecular activity and revealed that this modification governs antibody effector function.\",\n      \"evidence\": \"Sequential biallelic FUT8 knockout in CHO cells with ADCC and FcγRIIIa binding assays\",\n      \"pmids\": [\"15352059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve enzyme structure or catalytic residues\", \"Scope of native glycoprotein substrates not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Kinetic and structural characterization of donor binding clarified how FUT8 recognizes GDP-fucose and which residues drive catalysis.\",\n      \"evidence\": \"Recombinant human FUT8 kinetics, GDP-fucose analogue inhibition, and X-ray crystallography revealing coiled-coil, GT-B/Rossmann catalytic, and SH3 domains\",\n      \"pmids\": [\"16344263\", \"17172260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acceptor N-glycan binding mode not yet resolved\", \"Functional role of the SH3 domain not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Fut8 knockout mice connected core fucosylation to receptor signaling in vivo, showing that loss of fucosylation dysregulates TGF-β, EGF, PDGF, and LRP-1-dependent processes.\",\n      \"evidence\": \"Fut8-null mouse models with ligand rescue, gene reintroduction, endocytosis assay, and serum IGFBP-3 measurement\",\n      \"pmids\": [\"17132494\", \"16567404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether fucosylation acts directly on each receptor versus secondary effects not fully separated\", \"Site-specific glycan determinants not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking Fut8 loss to reduced VEGFR-2 and elevated ceramide-driven apoptosis extended the emphysema phenotype to a defined survival-receptor axis.\",\n      \"evidence\": \"Fut8 knockout mouse and siRNA in A549/TGP49 cells with TUNEL and ceramide measurements\",\n      \"pmids\": [\"19179362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling fucosylation loss to VEGFR-2 transcription unclear\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"FUT8 was shown to exert opposing, context-dependent effects on TGF-β-superfamily signaling and to control lineage outputs such as neuritogenesis and erythroid differentiation.\",\n      \"evidence\": \"siRNA/shRNA knockdown, overexpression, domain/loop mutagenesis, and rescue in PC12, MEL, and K562 cells\",\n      \"pmids\": [\"23796784\", \"23609441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of positive versus negative signaling outcomes not unified\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating GnT-I-independent fucosylation of high-mannose glycans broadened FUT8's substrate range beyond complex-type N-glycans.\",\n      \"evidence\": \"Stable FUT8 knockdown/overexpression in HEK293S GnT-I-/- cells with glycan mass spectrometry of EPO\",\n      \"pmids\": [\"27008861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of high-mannose core fucosylation not defined\", \"Single rigorous study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Glycoproteomic and functional studies established FUT8 as a driver of cancer invasion and metastasis acting through specific substrates such as TGF-β receptors and L1CAM.\",\n      \"evidence\": \"shRNA/CRISPR loss-of-function, lentiviral gain-of-function, ligand binding assays, glycoproteomics, and in vivo metastasis/dissemination models in breast cancer and melanoma\",\n      \"pmids\": [\"28982386\", \"28609658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of metastasis-relevant substrates incomplete\", \"Quantitative contribution of each target not ranked\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Domain dissection revealed that the SH3 domain (His-535) is required for catalysis and trafficking and recruits RPN1 to stimulate activity, while α-helical domains drive the active homodimer.\",\n      \"evidence\": \"Truncation/site-directed mutagenesis, in vivo cross-linking, cell-surface biotinylation, proteomics, and RPN1 knockdown\",\n      \"pmids\": [\"32350116\", \"32147455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the SH3/α-helical intermolecular interface not solved\", \"Mechanism of RPN1 stimulation at atomic level unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple ligand-bound crystal structures and acceptor specificity assays defined induced-fit donor binding and preference for the G0 biantennary glycan, refining substrate recognition rules.\",\n      \"evidence\": \"X-ray crystallography of FUT8 with GDP and four glycan acceptors plus active-site mutagenesis and kinetic analysis\",\n      \"pmids\": [\"33004438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics in the membrane-anchored enzyme not captured\", \"Acceptor recognition for non-canonical substrates incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"FUT8-EGFR core fucosylation was shown to control EGFR dimerization, trafficking, and downstream signaling across prostate cancer, keratinocytes, and tumor-associated fibroblasts.\",\n      \"evidence\": \"Overexpression/knockdown, EGFR surface and dimerization assays, trafficking assays, conditional KO psoriasis mouse, and CAF co-culture models\",\n      \"pmids\": [\"32085441\", \"32888953\", \"32266093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site-specific EGFR glycan determinants not fully mapped\", \"Whether effects generalize across tissues at endogenous levels untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Substrate-stabilization mechanisms were defined, showing FUT8 core fucosylation protects target glycoproteins (B7H3, IGF-1R, mucins, TNFRs) from degradation or mislocalization, broadening its roles in immunosuppression, mucus biology, and apoptosis control.\",\n      \"evidence\": \"Knockdown/overexpression, protein stability and trafficking assays, immune functional assays, Fut8-/- mouse colon analysis, and in vivo therapy combination\",\n      \"pmids\": [\"33976130\", \"30712666\", \"36252012\", \"34857735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect stabilization not always separated\", \"Glycosite-resolved mechanisms incomplete for some targets\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"STD NMR and glycopeptide assays refined the rules of FUT8 substrate selection, showing it reads both glycan structure and the underlying peptide and requires prior GDP binding for optimal acceptor recognition.\",\n      \"evidence\": \"STD NMR, in vitro assays with N-glycopeptide libraries, and CHO glycoengineering with glycoproteomics\",\n      \"pmids\": [\"35662980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative prediction of in vivo fucosylation site preference not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Glycoproteomics expanded the FUT8 target catalogue and identified adhesion and cytokine-signaling substrates (integrin αvβ5, IL6ST) supporting metastatic phenotypes.\",\n      \"evidence\": \"Quantitative glycoproteomics of FUT8-KO versus WT breast cancer cells with LCA blotting, LC-MS/MS, and adhesion assays\",\n      \"pmids\": [\"35303925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional validation limited to a subset of 140 targets\", \"Single-lab dataset\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transcriptional control of FUT8 was defined, placing it downstream of Wnt/β-catenin-TCF/LEF, Caveolin-1, c-Myc/c-Myb, and p53 in disease contexts.\",\n      \"evidence\": \"ChIP, RIP, EMSA, luciferase reporters, and overexpression/knockdown rescue in colorectal, hepatocellular, and microglial models\",\n      \"pmids\": [\"34021424\", \"32710651\", \"36692036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative weight of these regulators across tissues unknown\", \"Single-lab mechanisms\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistic studies tied FUT8 to degradation pathways and fibrosis signaling, showing defucosylation triggers chaperone-mediated autophagy of B7H3 and that FUT8-galectin-3 and FUT8-TLR3 axes drive fibrotic and inflammatory responses.\",\n      \"evidence\": \"Glycosite mutants, HSC70/LAMP2A co-IP, CMA assays, FUT8-Gal-3 co-IP, conditional FUT8 KO, and in vivo CRC, lung fibrosis, and renal IRI models\",\n      \"pmids\": [\"37537172\", \"36073215\", \"37432656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of CMA-coupled degradation to other substrates untested\", \"Direct versus indirect interactions for Gal-3 axis not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"FUT8 was established as a trafficking and stabilization factor for diverse glycoproteins—TMEM67 in cilia, SEMA7A, CD36, GLUT1, and Cntn2—linking core fucosylation to ciliogenesis, metabolism, apoptosis, and neuronal development.\",\n      \"evidence\": \"Co-IP, glycosite-specific mutants, autophagy/half-life assays, conditional and global Fut8 KO mice, and rescue experiments across cilia, neuron, kidney, and epithelial systems\",\n      \"pmids\": [\"40728580\", \"38548747\", \"39563263\", \"41027183\", \"39604780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific dominance among many substrates unclear\", \"Several findings from single labs\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanism-based small-molecule FUT8 inhibitors that bind only in the presence of GDP were developed, validating the catalytic mechanism and enabling cellular suppression of core fucosylation.\",\n      \"evidence\": \"High-throughput screening, SPR, mechanistic covalent-inhibition studies, and cell-based EGFR/T-cell signaling assays\",\n      \"pmids\": [\"39340265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo selectivity and pharmacology not fully characterized in this study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic and pharmacological evidence established FUT8 as a regulator of platelet receptor function, thrombosis, viral entry, atherosclerosis, and reproduction, identifying defined substrates including GPVI, αIIbβ3, aminopeptidase N, and Unc5b.\",\n      \"evidence\": \"Glycoproteomics, binding/aggregometry assays, glycosite mutants, platelet-specific and global Fut8 KO mice, FDW028 inhibitor, viral entry assays, and ApoE-/- and ovary models\",\n      \"pmids\": [\"42237907\", \"42149951\", \"36670464\", \"40262667\", \"40473957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window for FUT8 inhibition across these systems undefined\", \"Cross-species conservation of substrate sites incompletely mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FUT8 selects among its many substrates in a given cell type, and how its domain-mediated localization, dimerization, and RPN1 coupling are integrated to set fucosylation output in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking substrate-selection rules to in vivo glycoproteome\", \"Atomic structure of the catalytically competent dimer/RPN1 complex lacking\", \"Quantitative ranking of physiologically dominant substrates per tissue unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 9, 14, 18]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [16, 17, 23, 27, 32]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [21, 36]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 9, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 16, 20, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 23]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 35, 38]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RPN1\", \"TMEM67\", \"HSPA8\", \"LGALS3\", \"SEMA7A\", \"UNC5B\", \"EGFR\", \"B7H3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}