Affinage

GLT8D1

Glycosyltransferase 8 domain-containing protein 1 · UniProt Q68CQ7

Length
371 aa
Mass
41.9 kDa
Annotated
2026-06-10
11 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLT8D1 is a UDP-dependent galactosyltransferase that transfers galactose from UDP-galactose onto N-acetylgalactosamine through a retaining catalytic mechanism, adopting a GT-A fold and depending on Mn2+ and UDP nucleotides for stability (PMID:38066107). Its enzymatic activity is central to its cellular functions: in glioblastoma, GLT8D1 activity promotes tumor cell migration, with cytoskeleton- and intracellular transport-associated proteins recovered as candidate substrates (PMID:35198895). Under hypoxia, HIF-1α induces GLT8D1, which N-glycosylates and directly binds the stem cell marker CD133 to prevent its endosomal-lysosomal degradation, sustaining Wnt/β-catenin signaling and glioma stem cell self-renewal; GLT8D1 depletion triggers G2/M arrest and apoptosis (PMID:35301431). In neural stem cells, loss of GLT8D1 drives proliferation, impairs differentiation, and alters neuronal morphology and synaptic transmission (PMID:29483533). ALS-associated mutations R92C and G78W map to the substrate-binding site, impair enzyme activity, and confer cytotoxicity and motor deficits, linking GLT8D1 to amyotrophic lateral sclerosis (PMID:30811981).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2018 Medium

    Established a first cellular role for GLT8D1 by asking whether it influences neural stem cell fate, showing it constrains proliferation and is required for proper differentiation.

    Evidence shRNA knockdown in neural stem cells with proliferation, differentiation, morphology and electrophysiology readouts

    PMID:29483533

    Open questions at the time
    • Molecular mechanism linking GLT8D1 enzyme activity to the phenotypes not defined
    • No substrate identified in neural stem cells
    • Single lab, single system
  2. 2019 High

    Connected GLT8D1 to disease by asking whether its variants cause ALS, showing substrate-site mutations impair enzyme activity and produce motor neuron toxicity that tracks with clinical severity.

    Evidence Exome sequencing, in vitro enzyme activity assays of R92C/G78W mutants, zebrafish motor model and cytotoxicity assays

    PMID:30811981

    Open questions at the time
    • Physiological substrate whose loss drives motor neuron toxicity unknown
    • Mechanism linking reduced glycosyltransferase activity to neurodegeneration not resolved
  3. 2022 Medium

    Addressed whether GLT8D1 enzymatic activity drives cancer cell behavior, showing active-site mutations reducing glycosyltransferase activity impair glioblastoma migration and implicating cytoskeletal/transport proteins as substrates.

    Evidence Overexpression, active-site mutagenesis, in vitro glycosyltransferase assays, migration assays, LC-MS/MS interactome, structure prediction

    PMID:35198895

    Open questions at the time
    • Substrate identity is tentative (LC-MS/MS interactors only, no validated glycosylation site)
    • Direct glycosylation of cytoskeletal proteins not demonstrated
  4. 2022 High

    Defined a complete signaling axis by asking how hypoxia-induced GLT8D1 supports glioma stemness, showing it N-glycosylates and binds CD133 to block its lysosomal degradation and sustain Wnt/β-catenin signaling.

    Evidence Knockdown, reciprocal Co-IP, N-glycosylation and endosomal-lysosomal degradation assays, Wnt/β-catenin reporter, self-renewal assays, mouse models and PDX, inhibitor and dominant-negative peptide

    PMID:35301431

    Open questions at the time
    • Specific CD133 glycosylation site and stoichiometry not mapped
    • Whether other clients are stabilized similarly unknown
  5. 2023 High

    Resolved the core biochemistry by asking what reaction GLT8D1 catalyzes, defining it as a Mn2+/UDP-dependent retaining galactosyltransferase transferring galactose onto N-acetylgalactosamine with a GT-A fold.

    Evidence Recombinant protein purification, differential scanning fluorimetry, in vitro glycosyltransferase assay, structural modeling

    PMID:38066107

    Open questions at the time
    • Physiological acceptor substrates in vivo not established
    • No experimental crystal/cryo-EM structure
    • Link between defined in vitro activity and cellular phenotypes not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous physiological substrates of GLT8D1 and how its galactosyltransferase activity mechanistically produces motor neuron, neural stem cell, and glioma phenotypes remain unresolved.
  • No validated in vivo glycosylation substrate beyond candidate interactors
  • Subcellular localization not characterized in the corpus
  • Structural basis of substrate recognition not experimentally determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-1643685 Disease 2 R-HSA-392499 Metabolism of proteins 2 R-HSA-162582 Signal Transduction 1
Partners
CD133

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 ALS-associated mutations R92C and G78W in GLT8D1 map to the substrate binding site of the glycosyltransferase domain and impair GLT8D1 enzyme activity in vitro. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS, with relative toxicity mirroring clinical severity. Exome sequencing, in vitro enzyme activity assay, zebrafish motor deficit model, cytotoxicity assay Cell reports High 30811981
2023 GLT8D1 is a UDP-dependent galactosyltransferase that transfers galactose from UDP-galactose onto N-acetylgalactosamine. It is stabilized by Mn2+ and UDP nucleotides, is itself N-glycosylated, and adopts a GT-A fold consistent with CAZy family GT8, with a retaining catalytic mechanism. Recombinant protein production and purification, differential scanning fluorimetry, in vitro glycosyltransferase activity assay, structural modeling Scientific reports High 38066107
2022 The enzymatic (glycosyltransferase) activity of GLT8D1 promotes glioblastoma cell migration; point mutations introduced into the predicted active site reduced glycosyltransferase activity in vitro and impaired GBM tumor cell migration. LC-MS/MS of GLT8D1 interaction partners identified cytoskeleton- and intracellular transport-associated proteins as potential substrates. In vitro overexpression, active-site mutagenesis, in vitro glycosyltransferase activity assay, cell migration assay, LC-MS/MS interactome analysis, in silico 3D structure prediction iScience Medium 35198895
2022 Under hypoxia, HIF-1α induces GLT8D1 expression, and GLT8D1 stabilizes the stem cell marker CD133 by N-linked glycosylation and direct protein-protein interaction, preventing its degradation via the endosomal-lysosomal pathway. This GLT8D1/CD133 complex sustains Wnt/β-catenin signaling to promote glioma stem cell self-renewal and tumor growth. GLT8D1 knockdown promotes G2/M cell cycle arrest and apoptosis. GLT8D1 knockdown/depletion, co-immunoprecipitation (GLT8D1/CD133 complex), N-glycosylation analysis, endosomal-lysosomal pathway assay, Wnt/β-catenin reporter assay, in vitro self-renewal assays, glioma mouse models and patient-derived xenografts, dominant-negative CD133 peptide (FECD133) and lercanidipine inhibition Cell death and differentiation High 35301431
2018 GLT8D1 knockdown in neural stem cells promotes their proliferation and inhibits their differentiation, and alters neuronal morphology and synaptic transmission. shRNA knockdown in neural stem cells, proliferation and differentiation assays, neuronal morphology and electrophysiology measurements Nature communications Medium 29483533

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes. Nature communications 88 29483533
2019 Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis. Cell reports 65 30811981
2022 Hypoxia-induced GLT8D1 promotes glioma stem cell maintenance by inhibiting CD133 degradation through N-linked glycosylation. Cell death and differentiation 59 35301431
2019 Mutation analysis of GLT8D1 and ARPP21 genes in amyotrophic lateral sclerosis patients from mainland China. Neurobiology of aging 19 31653410
2023 Intergenic Interactions of SBNO1, NFAT5 and GLT8D1 Determine the Susceptibility to Knee Osteoarthritis among Europeans of Russia. Life (Basel, Switzerland) 13 36836762
2021 Genetic analysis of GLT8D1 and ARPP21 in Australian familial and sporadic amyotrophic lateral sclerosis. Neurobiology of aging 10 33581934
2022 Enzymatic activity of glycosyltransferase GLT8D1 promotes human glioblastoma cell migration. iScience 8 35198895
2023 Glycosyltransferase 8 domain-containing protein 1 (GLT8D1) is a UDP-dependent galactosyltransferase. Scientific reports 7 38066107
2021 GLT8D1 may not be significant in Chinese sporadic amyotrophic lateral sclerosis patients. Neurobiology of aging 5 33714647
2021 Germinal GLT8D1, GATAD2A and SLC25A39 mutations in a patient with a glomangiopericytal tumor and five different sarcomas over a 10-year period. Scientific reports 5 33963205
2020 Mutation screening and burden analysis of GLT8D1 in Chinese patients with amyotrophic lateral sclerosis. Neurobiology of aging 5 33581933

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