{"gene":"ST3GAL4","run_date":"2026-06-14T07:33:11","timeline":{"discoveries":[],"current_model":"Parse failed"},"narrative":{"mechanistic_narrative":"No mechanistic discoveries found in literature.","teleology":[],"mechanism_profile":null},"prefetch_data":{"uniprot":{"accession":"Q11206","full_name":"CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 4","aliases":["Alpha 2,3-sialyltransferase IV","Gal-NAc6S","Gal-beta-1,3-GalNAc-alpha-2,3-sialyltransferase","Gal-beta-1,4-GlcNAc-alpha-2,3-sialyltransferase","N-acetyllactosaminide alpha-2,3-sialyltransferase","SAT-3","ST-4","ST3Gal IV","ST3GalIV","ST3GalA.2","STZ","Sialyltransferase 4C","SIAT4-C"],"length_aa":333,"mass_kda":38.0,"function":"A beta-galactoside alpha2-3 sialyltransferase involved in terminal sialylation of glycoproteins and glycolipids (PubMed:8288606, PubMed:8611500, PubMed:37632720). Catalyzes the transfer of sialic acid (N-acetyl-neuraminic acid; Neu5Ac) from the nucleotide sugar donor CMP-Neu5Ac onto acceptor Galbeta-(1->3)-GalNAc- and Galbeta-(1->4)-GlcNAc-terminated glycoconjugates through an alpha2-3 linkage (PubMed:8288606, PubMed:8611500). Plays a major role in hemostasis. Responsible for sialylation of plasma VWF/von Willebrand factor, preventing its recognition by asialoglycoprotein receptors (ASGPR) and subsequent clearance. Regulates ASGPR-mediated clearance of platelets (By similarity). Participates in the biosynthesis of the sialyl Lewis X epitopes, both on O- and N-glycans, which are recognized by SELE/E-selectin, SELP/P-selectin and SELL/L-selectin. Essential for selectin-mediated rolling and adhesion of leukocytes during extravasation (PubMed:25498912). Contributes to adhesion and transendothelial migration of neutrophils likely through terminal sialylation of CXCR2 (By similarity). In glycosphingolipid biosynthesis, sialylates GM1 and GA1 gangliosides to form GD1a and GM1b, respectively (PubMed:8288606). Metabolizes brain c-series ganglioside GT1c forming GQ1c (By similarity). Synthesizes ganglioside LM1 (IV3Neu5Ac-nLc4Cer), a major structural component of peripheral nerve myelin (PubMed:8611500)","subcellular_location":"Golgi apparatus, Golgi stack membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/Q11206/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ST3GAL4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ST3GAL4","total_profiled":1310},"omim":[{"mim_id":"153330","title":"LYSOSOME-ASSOCIATED MEMBRANE PROTEIN 1; LAMP1","url":"https://www.omim.org/entry/153330"},{"mim_id":"128239","title":"DYSTROGLYCAN 1; DAG1","url":"https://www.omim.org/entry/128239"},{"mim_id":"108361","title":"ASIALOGLYCOPROTEIN RECEPTOR 2; ASGR2","url":"https://www.omim.org/entry/108361"},{"mim_id":"108360","title":"ASIALOGLYCOPROTEIN RECEPTOR 1; ASGR1","url":"https://www.omim.org/entry/108360"},{"mim_id":"104240","title":"ST3 BETA-GALACTOSIDE ALPHA-2,3-SIALYLTRANSFERASE 4; ST3GAL4","url":"https://www.omim.org/entry/104240"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ST3GAL4"},"hgnc":{"alias_symbol":["STZ","SAT3","FLJ11867"],"prev_symbol":["CGS23","SIAT4","NANTA3","SIAT4C"]},"alphafold":{"accession":"Q11206","domains":[{"cath_id":"3.90.1480.20","chopping":"44-330","consensus_level":"high","plddt":92.9305,"start":44,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q11206","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q11206-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q11206-F1-predicted_aligned_error_v6.png","plddt_mean":89.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ST3GAL4","jax_strain_url":"https://www.jax.org/strain/search?query=ST3GAL4"},"sequence":{"accession":"Q11206","fasta_url":"https://rest.uniprot.org/uniprotkb/Q11206.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q11206/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q11206"}},"corpus_meta":[{"pmid":"7926307","id":"PMC_7926307","title":"STZ transport and cytotoxicity. 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in turn induces increased invasive phenotype through specific activation of c-Met receptor tyrosine kinase, with downstream phosphorylation of FAK and Src proteins and activation of Cdc42, Rac1, and RhoA GTPases. Inhibition of c-Met and Src activation abolished the increased invasive phenotype.\",\n      \"method\": \"Stable transfection of ST3GAL4 into cancer cells, in vitro invasion assay, in vivo CAM model, phospho-tyrosine kinase array, Western blot for FAK/Src phosphorylation, GTPase activity assays, pharmacological inhibition\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable overexpression with functional readout in vitro and in vivo, multiple orthogonal methods (invasion assay, phosphoproteomics, GTPase assays, pharmacological inhibition), single lab\",\n      \"pmids\": [\"23799130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ST3Gal4-deficient myeloid cells show reduced binding of the chemokine Ccl5 and impaired Ccl5-triggered integrin activation, leading to almost complete abrogation of Ccl5-induced arrest on TNF-α-stimulated endothelium. St3Gal4 deficiency severely reduced Ccl5-triggered neutrophil and monocyte extravasation into the peritoneal cavity and drastically reduced atherosclerotic lesion size in Apoe(-/-) mice. Ccl2 binding and Ccl2-induced flow arrest were not significantly affected by St3Gal4 deficiency.\",\n      \"method\": \"St3Gal4 knockout mice, flow chamber adhesion assays, ex vivo perfusion, intravital microscopy, peritoneal recruitment assays, chemokine binding assays, atherosclerosis model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal functional readouts (chemokine binding, integrin activation, intravital microscopy, in vivo recruitment, atherosclerosis model) in a single study\",\n      \"pmids\": [\"24425712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Deletion of St3Gal4 in mice results in ventricular Nav (voltage-gated Na+ channel) gating at more depolarized potentials, slower inactivation, and faster recovery from fast inactivation compared to WT controls, consistent with reduced sialylation of cardiac Nav. ST3Gal4(-/-) myocytes showed a 20% increase in time to action potential peak and a 30 ms decrease in refractory period. Enzymatic desialylation confirmed that ST3Gal4(-/-) ventricular Nav are less sialylated. Nav surface expression and maximal Na+ current levels were unaffected. Optical mapping showed 27% reduction in minimum ventricular refractory period and increased susceptibility to arrhythmias in ST3Gal4(-/-) ventricles.\",\n      \"method\": \"St3Gal4 knockout mice, whole-cell patch-clamp, current-clamp recordings, enzymatic desialylation, optical mapping of epicardial conduction\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal electrophysiological methods (voltage-clamp, current-clamp, enzymatic desialylation, optical mapping) establishing mechanistic link between ST3GAL4-mediated sialylation and Nav channel gating\",\n      \"pmids\": [\"23471032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TNF increases the expression of the α2,3-sialyltransferase gene ST3GAL4 in human bronchial mucosa and A549 lung carcinoma cells, and the BX transcript isoform is the major form expressed. siRNA silencing of ST3GAL4 confirmed its role in sialyl-Lewis(x) (sLe(x)) biosynthesis in lung cells. Luciferase assays confirmed that the 2 kb genomic sequence surrounding the BX exon contains a promoter region regulated by TNF-related transcription factors.\",\n      \"method\": \"siRNA knockdown of ST3GAL4, flow cytometry for sLe(x) expression, RT-PCR, luciferase promoter assay, human bronchial mucosa tissue analysis\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with functional sLe(x) readout plus promoter luciferase validation, single lab\",\n      \"pmids\": [\"22691873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST3GAL4 KO cells specifically show decreased α2,3-sialylation of β1 integrin (while α2,3-sialylation of β1 integrin is increased in ST3GAL3 KO and ST3GAL6 KO cells). ST3GAL4 KO cells show suppressed E-cadherin and claudin-1 expression (opposite to ST3GAL3 and ST3GAL6 KO). Overexpression of ST3GAL4 in ST3GAL6 KO cells greatly enhanced α2,3-sialylation of β1 integrin specifically. These alterations were reversed by re-expression of the corresponding gene in rescued cells.\",\n      \"method\": \"Individual CRISPR/Cas9 knockout cell lines for ST3GAL3, ST3GAL4, ST3GAL6; lectin blotting; flow cytometry; Western blot; rescue overexpression experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KO and rescue experiments with multiple orthogonal methods establishing ST3GAL4 as the primary α2,3-sialyltransferase for β1 integrin N-glycans\",\n      \"pmids\": [\"31914669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Among ST3GAL3, ST3GAL4, and ST3GAL6, siRNA knockdown of ST3GAL4 in CHO cells producing erythropoietin (EPO) caused the largest reduction in α2,3-sialylation of EPO among single siRNA transfections, as measured by HPLC sialic acid quantification and N-glycan analysis. This identifies ST3GAL4 as playing a critical role in glycoprotein sialylation of recombinant EPO.\",\n      \"method\": \"siRNA knockdown (single, double, triple), ELLA lectin assays, HPLC sialic acid quantification, N-glycan structural analysis of EPO\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with HPLC quantification and N-glycan analysis, single lab, multiple siRNA combinations tested\",\n      \"pmids\": [\"25998389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST3GAL4 is transported from the Golgi to post-Golgi compartments (PGCs) by Rab11-dependent post-Golgi transport. Knockdown of Rab11 causes ST3GAL4 to accumulate densely in the trans-Golgi network rather than distributing to peripheral puncta, selectively enhancing α2,3-sialylation of N-glycans without altering ST3GAL4 mRNA, protein levels, or donor substrate levels. ST6GAL1 localization was unaffected by Rab11 knockdown. This identifies Rab11-mediated transport of ST3GAL4 to PGCs as a negative regulator of α2,3-sialylation.\",\n      \"method\": \"Rab11 siRNA knockdown in HeLa cells, lectin analysis, LC-MS glycan structural analysis, fluorescence microscopy for ST3GAL4 subcellular localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockdown with multiple orthogonal methods (lectin assay, LC-MS glycomics, fluorescence microscopy), mechanistic link between localization change and glycosylation output established, single lab\",\n      \"pmids\": [\"33524390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ST3GAL4 catalyzes sialylation of MET receptor tyrosine kinase at N785, which antagonizes K48-linked ubiquitin-dependent MET degradation and subsequently activates MET and its downstream proliferation signaling pathways. ST3GAL4 overexpression induces acquired resistance to the EGFR-TKI osimertinib in NSCLC cells in vitro and in vivo. ST3GAL4 knockdown or inhibition by brigatinib resensitizes resistant NSCLC cells to osimertinib.\",\n      \"method\": \"ST3GAL4 overexpression and knockdown in NSCLC cell lines, in vitro and in vivo drug resistance assays, mass spectrometry identification of sialylation site (N785), ubiquitination assays, Western blot for MET activation and downstream signaling\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific sialylation identified by MS, mechanistic link to ubiquitin-dependent degradation established, functional rescue with pharmacological inhibitor, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"38408602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRISPR-Cas9 knockout of ST3GAL4 in AML cells dramatically reduces Siglec-9 ligand expression. Mass spectrometry analysis revealed that Siglec-9 primarily binds N-linked sialoglycans on AML cells. ST3GAL4 KO enhanced sensitivity of AML cells to phagocytosis by Siglec-9-expressing macrophages, identifying ST3GAL4 as the primary synthesizer of Siglec-9 ligands driving immune evasion.\",\n      \"method\": \"CRISPR-Cas9 KO, CRISPR genomic screening, flow cytometry for Siglec-9 ligand expression, mass spectrometry of cell-surface glycosylation, phagocytosis assays with Siglec-9-expressing macrophages\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO validated by MS glycoproteomic analysis and functional phagocytosis assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39551873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CMAS and ST3GAL4 are essential host genes for influenza A virus (IAV) attachment and entry. ST3GAL4 knockout prevented the adsorption of swine and avian IAV (with more distinct effect on avian IAV) but had no effect on the adsorption of human IAV, consistent with ST3GAL4's role in synthesizing α2,3-linked sialic acid receptors preferentially recognized by avian/swine strains.\",\n      \"method\": \"CMAS and ST3GAL4 CRISPR knockout cells, viral adsorption assays with swine, avian, and human IAV strains\",\n      \"journal\": \"International journal of molecular sciences\",\n      ","stage2_raw":"","audit_flag":{"gene":"ST3GAL4","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"recall_miss","uniprot_band":"rich","rules_fired":"R5","issue":"R5: no narrative despite experimental UniProt FUNCTION (1416 chars) and on-target evidence in corpus (100 on-target corpus titles)"},"evaluation":null}