Affinage

B3GALT2

Beta-1,3-galactosyltransferase 2 · UniProt O43825

Length
422 aa
Mass
49.2 kDa
Annotated
2026-04-28
19 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

B3GALT2 is a UDP-galactose:β-N-acetyl-glucosamine β-1,3-galactosyltransferase that catalyzes the transfer of galactose in β-1,3 linkage to GlcNAc acceptors on N-glycans and glycoprotein substrates, functioning in glycosylation-dependent signaling and neuronal homeostasis (PMID:9582303, PMID:11058588). B3GALT2 galactosylates TGF-βRII and ALK1 to activate TGF-β/Smad signaling, thereby promoting blood-brain barrier integrity, cerebral angiogenesis, and neuroprotection after ischemic injury (PMID:33524473, PMID:41565095). Beyond TGF-β signaling, B3GALT2 suppresses NLRP3 inflammasome-mediated pyroptosis downstream of transcriptional activation by TFAP2A, modulates neuroinflammation through the TLR4/NF-κB axis, regulates F3/Contactin and Reelin/Dab1 neuroprotective pathways, and enhances antisense oligonucleotide cellular uptake by upregulating endocytic scavenger receptors (PMID:41654938, PMID:28257892, PMID:36509381, PMID:33482286, PMID:41341746). Genetic knockout in mice causes spatial learning deficits, neuronal loss, and synaptic dysfunction in the hippocampus, establishing a requirement for B3GALT2 in normal brain function (PMID:36504040).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1998 High

    Establishing the enzymatic identity of B3GALT2 as a β-1,3-galactosyltransferase resolved what catalytic activity the gene encodes and provided the biochemical foundation for all subsequent functional studies.

    Evidence Recombinant expression in Baculovirus system with kinetic characterization of galactose transfer to GlcNAc acceptors

    PMID:9582303

    Open questions at the time
    • Physiological glycoprotein substrates were not identified
    • No tissue-specific expression or in vivo function addressed
    • Structural basis for substrate specificity not determined
  2. 2000 Medium

    Demonstrating that B3GALT2 directs sialyl-Lewis x synthesis on N-glycans (type 2 chains) in living cells defined the glycan products it generates in a cellular context and distinguished it from the related β3Gal-T5.

    Evidence CHO cell co-transfection with Fuc-TIII, endo-β-galactosidase glycan analysis, and flow cytometry for Lewis antigens

    PMID:11058588

    Open questions at the time
    • Endogenous cell types where B3GALT2 is the rate-limiting galactosyltransferase for Lewis antigen synthesis were not identified
    • Functional consequences of sialyl-Lewis x on specific glycoproteins not explored
  3. 2017 Medium

    Showing that B3galt2 knockdown reduces TLR4/NF-κB signaling and cytokine secretion in sensory neurons established B3GALT2 as a regulator of innate immune signaling in the nervous system, extending its role beyond glycan biosynthesis.

    Evidence siRNA knockdown in rat trigeminal ganglion neurons with ELISA, western blot, and immunohistochemistry readouts

    PMID:28257892

    Open questions at the time
    • Whether B3GALT2 directly glycosylates TLR4 or acts indirectly was not determined
    • Findings from a single lab in one neuronal cell type
  4. 2021 Medium

    Gain- and loss-of-function studies in ischemic stroke models placed B3GALT2 upstream of both TGF-β/Smad2/3 signaling (for BBB protection) and Reelin/Dab1 signaling (for neuronal survival), revealing two distinct downstream effector pathways for its neuroprotective action.

    Evidence Lentiviral overexpression and heterozygous KO mice subjected to MCAO, with intracerebroventricular TGF-β1 and recombinant Reelin rescue experiments

    PMID:33482286 PMID:33524473

    Open questions at the time
    • Whether B3GALT2 directly glycosylates Reelin or Dab1 was not tested
    • Heterozygous KO may not reveal full loss-of-function phenotype
    • Pathway cross-talk between TGF-β and Reelin arms not addressed
  5. 2022 Medium

    Genetic knockout revealed that B3GALT2 is required for normal hippocampal function, spatial learning, and synaptic integrity in adult mice, and that it regulates F3/Contactin-mediated neuroprotection and NLRP3 inflammasome suppression in vivo.

    Evidence Homozygous and heterozygous KO mice with Morris Water Maze, X-gal localization; intranasal recombinant B3galt2 with TGF-β1-siRNA rescue in MCAO; lentiviral overexpression/knockdown in diabetic mice

    PMID:36094000 PMID:36504040 PMID:36509381

    Open questions at the time
    • Glycoprotein substrates responsible for synaptic phenotype not identified
    • All in vivo neuroprotection studies from a single research group
    • Molecular link between B3GALT2 and F3/Contactin expression change (glycosylation vs. transcription) not resolved
  6. 2025 Medium

    A genome-wide screen identified B3GALT2 as a modulator of antisense oligonucleotide cellular uptake, mechanistically linked to upregulation of endocytic scavenger receptors and clathrin-mediated endocytosis, revealing an unexpected role in regulating receptor-mediated endocytic trafficking.

    Evidence ORF overexpression screen with splice reporter in HEK293/U2OS cells, transcriptomic and gene set enrichment analysis

    PMID:41341746

    Open questions at the time
    • Whether scavenger receptor upregulation requires B3GALT2 catalytic activity was not tested
    • Mechanism connecting galactosyltransferase activity to transcriptional changes in endocytic genes is unknown
    • Single lab finding
  7. 2026 Medium

    Identification of TGF-βRII and ALK1 as direct glycosylation substrates of B3GALT2, and of TFAP2A as a transcriptional activator of B3GALT2, provided the first molecular mechanism connecting B3GALT2 catalytic activity to specific receptor activation and placed B3GALT2 within a defined transcriptional regulatory circuit that suppresses NLRP3 inflammasome-mediated pyroptosis.

    Evidence Galactosylation measurement of TGF-βRII/ALK1 by western blot, ALK1 inhibitor ML347 rescue in MCAO mice; ChIP-qPCR and dual-luciferase for TFAP2A binding, epistasis in THP-1 cells

    PMID:41565095 PMID:41654938

    Open questions at the time
    • Specific glycosylation sites on TGF-βRII and ALK1 not mapped
    • Whether TFAP2A-B3GALT2-NLRP3 axis operates in vivo not confirmed
    • Both studies from single labs; independent replication pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise glycosylation sites on TGF-βRII, ALK1, and other substrates, the structural basis for B3GALT2 substrate selectivity, and the mechanism by which its galactosyltransferase activity influences transcription of endocytic and inflammatory genes remain unresolved.
  • No crystal or cryo-EM structure of B3GALT2
  • Full glycoproteomic identification of endogenous substrates not performed
  • Whether catalytic activity is required for all reported signaling effects (vs. scaffolding) not tested with catalytic-dead mutants

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3
Localization
GO:0005576 extracellular region 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ACVRL1CNTN1DAB1NLRP3RELNTFAP2ATGFBR2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 B3GALT2 encodes a UDP-galactose:β-N-acetyl-glucosamine β-1,3-galactosyltransferase, demonstrated by expression in the Baculovirus system showing transfer of galactose in β-1,3 linkage to GlcNAc acceptors, with kinetic properties similar to β3Gal-T1. Baculovirus expression system, enzymatic activity assay The Journal of biological chemistry High 9582303
2000 B3GALT2 (β3Gal-T2), when expressed in CHO cells with Fuc-TIII, directs synthesis of sialyl-Lewis x on N-glycans (type 2 chains), in contrast to β3Gal-T5 which directs Lewis type 1 antigen synthesis; β3Gal-T2 does not efficiently direct Lewis type 1 antigen synthesis. CHO cell transfection, endo-β-galactosidase treatment of N-glycans, flow cytometry/immunochemical detection of Lewis antigens The Journal of biological chemistry Medium 11058588
2017 B3galt2 knockdown in trigeminal ganglion neurons reduces secretion of TNFα and IL-6 and inhibits expression of TLR4 and NF-κB, placing B3galt2 upstream of the TLR4/NF-κB signaling pathway in neuroinflammation induced by dental pulp LPS exposure. siRNA knockdown, ELISA, immunohistochemistry, western blot in rat trigeminal ganglion model Neuroscience Medium 28257892
2021 B3galt2 is expressed in brain microvascular endothelial cells; overexpression via lentiviral vector reduces infarct volume and preserves blood-brain barrier integrity after MCAO, and this is associated with upregulation of TGF-β1, TGF-βRII, and p-Smad2/3; B3galt2 heterozygous knockout mice show reduced TGF-β signaling and increased BBB damage, placing B3galt2 upstream of the TGF-β/Smad2/3 pathway in endothelial cells. Lentiviral overexpression, heterozygous knockout mouse model, MCAO, western blot, BBB permeability assay, intracerebroventricular r-TGF-β1 rescue Neurochemistry international Medium 33524473
2021 B3galt2 heterozygous knockout mice exhibit exacerbated ischemic brain damage and decreased Reelin and Dab1 levels after MCAO; intracerebroventricular recombinant human Reelin rescues infarct volume and neuronal loss in B3galt2+/- mice, placing B3galt2 upstream of the Reelin/Dab1 signaling pathway in neuronal survival. Heterozygous knockout mouse model, MCAO, intracerebroventricular rh-Reelin rescue, western blot, caspase-3 activity assay Brain research bulletin Medium 33482286
2022 B3galt2 genetic knockout (homozygous and heterozygous) in adult mice impairs spatial learning, causes neuronal loss, and produces synaptic dysfunction in hippocampus and somatosensory cortex; X-gal staining in heterozygous mice confirms high B3galt2 expression in hippocampal dentate gyrus. Homozygous/heterozygous knockout mice, Morris Water Maze, X-gal staining, immunofluorescence Neuroreport Medium 36504040
2022 Recombinant human B3galt2 administered intranasally after MCAO reduces infarct volume, BBB permeability, neuronal apoptosis, and oxidative stress; these neuroprotective effects are abolished by intracerebroventricular TGF-β1-siRNA, placing B3galt2 upstream of the TGF-β1 pathway; B3galt2 also inhibits NF-κB, IL-6, TNF-α, IL-1β, and NLRP3 inflammasome activation. Intranasal recombinant protein administration, TGF-β1-siRNA knockdown rescue experiment, MCAO mouse model, infarct volume, ELISA, western blot FASEB journal Medium 36094000
2022 B3galt2 and F3/Contactin are co-localized in hippocampal regions; B3galt2 overexpression upregulates F3/Contactin expression, protects synapsin, and reduces neuronal apoptosis in diabetic mice; B3galt2 knockdown worsens cognitive impairment in diabetic mice, establishing B3galt2 as a regulator of F3/Contactin-mediated neuroprotection. Lentiviral overexpression, heterozygous knockout mice, immunohistochemistry co-localization, Morris Water Maze, western blot Neuroscience Medium 36509381
2025 B3GALT2 overexpression in HEK293 and U2OS cells significantly enhances cellular uptake and activity of antisense oligonucleotides (ASOs) across multiple targets; this is mechanistically linked to upregulation of endocytic scavenger receptors CUBN and SCARA5, and enrichment of clathrin-mediated endocytosis gene sets, identifying B3GALT2 as a modulator of ASO cellular entry. Genome-wide ORF overexpression screen with splice reporter, ASO activity assays, transcriptomic analysis, gene set enrichment analysis, ASO uptake quantification Molecular therapy. Nucleic acids Medium 41341746
2026 TFAP2A directly binds to the B3GALT2 promoter (confirmed by ChIP-qPCR and dual-luciferase reporter assay) to transcriptionally activate B3GALT2; B3GALT2 overexpression inhibits NLRP3 inflammasome activation and pyroptosis (reducing NLRP3, ASC, caspase-1 p20, GSDMD-N, LDH, IL-1β/IL-18) in LPS/MSU-stimulated THP-1 cells; B3GALT2 knockdown abolishes the anti-pyroptotic effects of TFAP2A overexpression. ChIP-qPCR, dual-luciferase reporter assay, gain- and loss-of-function in THP-1 cells, western blot, LDH assay, ELISA Journal of orthopaedic surgery and research Medium 41654938
2026 Recombinant human B3galt2 promotes cerebral angiogenesis during ischemic repair by activating the TGF-βRII/ALK1/Smad1/5 pathway; B3galt2 treatment increases galactosylation levels of TGF-βRII and ALK1 (glycosylation modification), and the pro-angiogenic and neuroprotective effects are abolished by the ALK1 inhibitor ML347, establishing B3galt2's mechanism as glycosylation of TGF-βRII/ALK1 to activate downstream Smad1/5 signaling. Intranasal rh-B3galt2, MCAO mouse model, ALK1 inhibitor (ML347) rescue, western blot for galactosylation, VEGFA/tight junction protein measurement Experimental neurology Medium 41565095

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A family of human beta3-galactosyltransferases. Characterization of four members of a UDP-galactose:beta-N-acetyl-glucosamine/beta-nacetyl-galactosamine beta-1,3-galactosyltransferase family. The Journal of biological chemistry 138 9582303
2000 beta 1,3-Galactosyltransferase beta 3Gal-T5 acts on the GlcNAcbeta 1-->3Galbeta 1-->4GlcNAcbeta 1-->R sugar chains of carcinoembryonic antigen and other N-linked glycoproteins and is down-regulated in colon adenocarcinomas. The Journal of biological chemistry 51 11058588
2011 Detection of the first gross CDC73 germline deletion in an HPT-JT syndrome family. Genes, chromosomes & cancer 35 21837707
2022 Clinical Eosinophil-Associated Genes can Serve as a Reliable Predictor of Bladder Urothelial Cancer. Frontiers in molecular biosciences 27 35936781
2021 Extracellular vesicle-derived AEBP1 mRNA as a novel candidate biomarker for diabetic kidney disease. Journal of translational medicine 27 34332599
2022 Intranasal administration of β-1, 3-galactosyltransferase 2 confers neuroprotection against ischemic stroke by likely inhibiting oxidative stress and NLRP3 inflammasome activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 36094000
2021 β-1, 3-galactosyltransferase 2 deficiency exacerbates brain injury after transient focal cerebral ischemia in mice. Brain research bulletin 14 33482286
2022 Altered expression of glycobiology-related genes in Parkinson's disease brain. Frontiers in molecular neuroscience 12 36504680
2017 Role of β-1,3-galactosyltransferase 2 in trigeminal neuronal sensitization induced by peripheral inflammation. Neuroscience 11 28257892
2021 β-1, 3-galactosyltransferase 2 ameliorates focal ischemic cerebral injury by maintaining blood-brain barrier integrity. Neurochemistry international 9 33524473
2022 Salidroside Alleviates Diabetic Cognitive Dysfunction Via B3galt2/F3/Contactin Signaling Pathway in Mice. Neuroscience 8 36509381
2022 Differential Long Non-Coding RNA Expression Analysis in Chronic Non-Atrophic Gastritis, Gastric Mucosal Intraepithelial Neoplasia, and Gastric Cancer Tissues. Frontiers in genetics 7 35571069
2017 Differential Gene Transcription of Extracellular Matrix Components in Response to In Vivo Corneal Crosslinking (CXL) in Rabbit Corneas. Translational vision science & technology 6 29242757
2025 Comparisons of miRNA profiles of exosomes derived from human iPSCs, ADSCs, and BMSCs and effects on chondrocyte function. Bone & joint research 2 40823751
2022 Effects of the genetic knockout of the β-1,3-galactosyltransferase 2 on spatial learning and neurons in the adult mouse hippocampus and somatosensory cortex. Neuroreport 2 36504040
2020 Identification of microRNA-target genes in mice hippocampus at 1 week after pilocarpine-induced status epilepticus. Biochemical and biophysical research communications 2 32800559
2026 β-1, 3-galactosyltransferase 2 promotes cerebral angiogenesis and neurological recovery during the ischemic repair phase through glycosylation modification of TGF-βR(II)/ALK1. Experimental neurology 0 41565095
2026 TFAP2A transcriptionally regulates B3GALT2 to affect gouty arthritis progression through pyroptosis: a study based on machine learning and multi-omics integration analysis. Journal of orthopaedic surgery and research 0 41654938
2025 An unbiased whole-genome open reading frame overexpression screen identifies B3GALT2, a novel inducer of cellular ASO activity. Molecular therapy. Nucleic acids 0 41341746