ST3GAL1

ST3GAL1 is a type II transmembrane sialyltransferase that transfers α2,3-linked sialic acid from CMP-sialic acid to Galβ1,3GalNAc (core 1) O-glycan structures on a broad range of glycoprotein substrates, thereby modulating receptor signaling, immune recognition, and cell adhesion. Identified substrates include AXL, VASN, GFRA1, EGFR, NRP1, CD55, CD18, CD34, CD43, GPIbα, MUCL1, and VEGF-A; sialylation of these targets controls diverse downstream pathways including AXL dimerization/activation, TGF-β1/Smad signaling, GDNF/RET/AKT signaling, EGFR/PI3K-AKT signaling, FAK/paxillin signaling, NF-κB activation, and LFA-1 endocytic recycling in T cells (PMID:27166796, PMID:33203881, PMID:30040982, PMID:30252131, PMID:37069398, PMID:40024474, PMID:39069074, PMID:40497576). ST3GAL1 also generates Siglec-7/9 ligands and modifies CD55 to confer complement resistance, establishing it as a glyco-immune checkpoint that promotes immune evasion (PMID:33177111, PMID:38448753). ST3GAL1 transcription is regulated by SOX2-GLI1, c-FOS/RANKL, TGF-β1, GDNF, and androgen-AR signaling, and is post-transcriptionally repressed by miR-4701-5p and miR-320b, integrating ST3GAL1 into multiple oncogenic and physiological feedback circuits (PMID:33203881, PMID:30252131, PMID:30040982, PMID:41680135, PMID:27088512, PMID:39069074).

1. 2016 High

   Establishing the core enzymatic identity of ST3GAL1: recombinant ST3GAL1 was shown to require native disulfide bonds for activity and to transfer sialic acid from CMP-sialic acid to β-d-galactoside substrates including lactose and N-acetyllactosamine in vitro, defining it as a bona fide sialyltransferase with characterized substrate preferences.

   Evidence Recombinant expression in E. coli with oxidative folding chaperones, in vitro sialylation assays with defined substrates

   PMID:27166796

   Open questions at the time

   • No crystal structure of human ST3GAL1 available
   • Kinetic parameters for physiological O-glycan substrates not determined in this study
   • Catalytic mechanism at atomic resolution unresolved
2. 2018 Medium

   Linking ST3GAL1 to specific receptor signaling cascades: ST3GAL1 was found to sialylate GFRA1, enabling GDNF-induced RET/AKT/ERα activation in breast cancer, with GDNF transcriptionally inducing ST3GAL1 to form a positive feedback loop — establishing the paradigm that ST3GAL1 modifies individual receptor glycoproteins to control ligand-driven signaling.

   Evidence ST3GAL1 silencing with phosphorylation assays for RET, AKT, ERα in ER+ breast cancer cells; GDNF stimulation and ST3GAL1 transcript measurement

   PMID:30040982

   Open questions at the time

   • Specific O-glycan sites on GFRA1 modified by ST3GAL1 not mapped
   • Whether sialylation alters GFRA1-GDNF binding affinity not directly measured
3. 2019 High

   Demonstrating that ST3GAL1 sialylation can attenuate rather than enhance signaling: sialylation of vasorin (VASN) reduced its binding to TGF-β1 by 2–3 fold, dampening Smad2/3 signaling and angiogenesis, while TGF-β1 itself transcriptionally induced ST3GAL1, revealing a negative feedback loop distinct from the positive feedback with GDNF/GFRA1.

   Evidence LC-MS/MS O-glycan analysis, neuraminidase treatment, HUVEC tube formation, Smad activation assays, MCF7 xenografts

   PMID:30252131

   Open questions at the time

   • Whether VASN sialylation affects other TGF-β superfamily ligands unknown
   • Structural basis for how sialylation reduces VASN-TGF-β1 binding not determined
4. 2020 High

   Expanding substrate repertoire to immune regulators and oncogenic receptors: ST3GAL1 was shown to sialylate CD55 (generating disialyl core 2 O-glycans that protect cancer cells from complement lysis and ADCC) and AXL (inducing dimerization/activation downstream of SOX2-GLI1), broadening the functional scope from growth factor signaling to immune evasion and oncogene activation.

   Evidence Mass spectrometry of CD55 O-glycans after ST3GAL1 knockdown, complement lysis/ADCC assays; AXL dimerization assays with in vivo melanoma models

   PMID:33177111 PMID:33203881

   Open questions at the time

   • Whether CD55 sialylation also affects complement regulatory function beyond protecting from lysis not tested
   • Whether other sialyltransferases compensate for ST3GAL1 loss on AXL or CD55 not examined
5. 2020 Medium

   Revealing context-dependent signaling outcomes: in renal cell carcinoma, ST3GAL1-mediated sialylation of EGFR inhibited EGFR phosphorylation and suppressed PI3K-AKT signaling, contrasting with contexts where ST3GAL1 promotes oncogenic signaling, and ST3GAL1 transcription was regulated by the lncRNA MEG3 via c-Jun.

   Evidence MEG3 overexpression/knockdown, c-Jun binding to ST3GAL1 promoter, EGFR sialylation and phosphorylation assays

   PMID:32737220

   Open questions at the time

   • Whether EGFR inhibition by sialylation is specific to the O-glycan versus N-glycan context not resolved
   • Apparent contradiction with studies showing ST3GAL1 promotes oncogenic EGFR signaling in other contexts not mechanistically reconciled
6. 2022 High

   Establishing physiological hematopoietic substrates and functional redundancy with ST3GAL2: double knockout of ST3GAL1/ST3GAL2 in iPSC-derived megakaryocytes identified CD34, CD43, and GPIbα as major O-glycan substrates and revealed that both enzymes are required for proplatelet formation, defining a non-cancer physiological role.

   Evidence ST3GAL1/ST3GAL2 double-KO iPSC lines, PNA lectin binding, megakaryocyte differentiation, substrate identification

   PMID:35507766

   Open questions at the time

   • Individual contributions of ST3GAL1 versus ST3GAL2 to each substrate not fully deconvolved
   • In vivo platelet phenotype in animal models not reported
7. 2023 High

   Discovering a T cell-intrinsic role: an in vivo CRISPR screen identified ST3GAL1 as a glycosylation modifier of CD18 in CD8+ T cells; ST3GAL1-mediated CD18 sialylation altered LFA-1 endocytic recycling, causing nonspecific tissue sequestration and impairing CAR T cell tumor homing, establishing ST3GAL1 as a cell-autonomous regulator of T cell trafficking.

   Evidence Pooled in vivo CRISPR-Cas9 loss-of-function screen, glycoprotein analysis, LFA-1 recycling assays, CAR T cell homing experiments

   PMID:37069398

   Open questions at the time

   • Whether ST3GAL1 deletion improves human CAR T cell efficacy in clinical settings unknown
   • Mechanism by which βII-spectrin reverses ST3GAL1-dependent LFA-1 mislocalization not fully elucidated
8. 2024 Medium

   Connecting ST3GAL1 to inhibitory Siglec ligand synthesis and androgen regulation: ST3GAL1-synthesized sialoglycans serve as ligands for Siglec-7/9 in prostate cancer, with androgen-AR signaling negatively regulating ST3GAL1 expression, providing a mechanistic link between hormone signaling and glyco-immune evasion.

   Evidence Siglec-7/9 ligand expression analysis, ST3GAL1 manipulation, androgen signaling modulation, enzalutamide treatment in prostate cancer cells

   PMID:38448753

   Open questions at the time

   • Specific glycoprotein carriers of Siglec-7/9 ligands generated by ST3GAL1 not identified
   • Whether enzalutamide-mediated ST3GAL1 induction enhances immune evasion in patients not tested
9. 2025 Medium

   Identifying NRP1 and VEGF-A as ST3GAL1 substrates with distinct signaling outputs: sialylation of NRP1 increased its affinity for EGFR and activated downstream CAPN2/migration signaling, while sialylation of VEGF-A activated FAK/paxillin signaling in endometrial cancer, further expanding the substrate-to-pathway map.

   Evidence ST3GAL1 silencing, NRP1-EGFR binding affinity measurements, CAPN2 activity assays; Duolink PLA and Co-IP for VEGF-A, xenograft models with soyasaponin I inhibitor

   PMID:40024474 PMID:40497576

   Open questions at the time

   • Whether NRP1 sialylation by ST3GAL1 occurs at O-glycan or N-glycan sites not resolved
   • Specificity of soyasaponin I for ST3GAL1 over other sialyltransferases in vivo not established
10. 2026 Medium

    Resolving transcriptional regulation in osteoclasts and identifying MUCL1 as a stability-modulating substrate: RANKL/c-FOS drives ST3GAL1 transcription in osteoclasts with estrogen-ERα opposing this via TRAF6 competition, linking ST3GAL1 to bone homeostasis; separately, ST3GAL1 sialylation of MUCL1 stabilizes the protein to promote breast cancer metastasis.

    Evidence RANKL stimulation with c-FOS/ERα binding studies, scRNA-seq of human bone, sialidase treatment in estrogen-deficient models; Co-IP, MUCL1 stability/degradation assays, in vivo metastasis models

    PMID:41680135 PMID:41770470

    Open questions at the time

    • Whether ST3GAL1 sialylation of specific osteoclast substrates mediates the bone loss phenotype not determined
    • Degradation pathway (proteasomal vs. lysosomal) for desialylated MUCL1 not identified

• A high-resolution structural model of human ST3GAL1 with bound substrate/donor, a comprehensive map of the O-glycosites it modifies on each substrate, and in vivo genetic studies distinguishing ST3GAL1 from compensating sialyltransferases in normal tissue homeostasis remain outstanding gaps.
• No crystal or cryo-EM structure of human ST3GAL1
• Site-specific O-glycan modification mapping incomplete for most substrates
• Conditional knockout phenotypes in non-cancer tissues largely uncharacterized