Details for: HS3ST3A1

Gene ID: 9955

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: HS3ST3A1

Ensembl ID: ENSG00000153976

Description: heparan sulfate-glucosamine 3-sulfotransferase 3A1

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • H2 horizontal cell CL0004218
    CSI 6.45
    rCSI 32.05%
    PRS 92.1
  • H1 horizontal cell CL0004217
    CSI 3.95
    rCSI 15.64%
    PRS 91.7
  • neural crest cell CL0011012
    CSI 3.46
    rCSI 2.74%
    PRS 92.66
  • retina horizontal cell CL0000745
    CSI 3.43
    rCSI 5.23%
    PRS 93.86
  • fibroblast of lung CL0002553
    CSI 3.17
    rCSI 2.95%
    PRS 97.04
  • ependymal cell CL0000065
    CSI 3.11
    rCSI 6.31%
    PRS 83.54
  • alveolar type 1 fibroblast cell CL4028004
    CSI 3.09
    rCSI 3.39%
    PRS 97.01
  • Mueller cell CL0000636
    CSI 3.02
    rCSI 6.9%
    PRS 92.23
  • hepatic stellate cell CL0000632
    CSI 2.84
    rCSI 10.64%
    PRS 94.14
  • VIP GABAergic cortical interneuron CL4023016
    CSI 2.75
    rCSI 3.29%
    PRS 88.8
  • choroid plexus epithelial cell CL0000706
    CSI 2.41
    rCSI 3.95%
    PRS 91.92
  • Schwann cell CL0002573
    CSI 2.25
    rCSI 6.38%
    PRS 93.71
  • chondrocyte CL0000138
    CSI 2.22
    rCSI 3.53%
    PRS 93.29
  • glioblast CL0000030
    CSI 1.75
    rCSI 2.79%
    PRS 91.19
  • cardiac muscle cell CL0000746
    CSI 1.69
    rCSI 2.43%
    PRS 90.78
  • cardiac neuron CL0010022
    CSI 1.39
    rCSI 4.45%
    PRS 95.3
  • astrocyte of the cerebral cortex CL0002605
    CSI 1.37
    rCSI 3.08%
    PRS 89.02
  • podocyte CL0000653
    CSI 1.3
    rCSI 5.78%
    PRS 95.78
  • stromal cell CL0000499
    CSI 1.29
    rCSI 3.63%
    PRS 93.9
  • regular atrial cardiac myocyte CL0002129
    CSI 1.17
    rCSI 3.78%
    PRS 93.16
  • enteroglial cell CL4040002
    CSI 0.97
    rCSI 5.1%
    PRS 95.99
  • endothelial cell of placenta CL0009092
    CSI 0.84
    rCSI 4.15%
    PRS 97.12

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [HS3ST3A1](/details-gene/9955) encodes heparan sulfate-glucosamine 3-sulfotransferase 3A1, a Golgi-resident enzyme critical for the final modification steps of heparan sulfate (HS) biosynthesis. Its primary function is to catalyze the transfer of a sulfo group to the 3-O position of glucosamine residues within the heparan sulfate chain, a key step in generating specific HS structures. This modification is crucial for mediating protein-glycan interactions involved in cell signaling and pathogen entry. **Overall**, expression data reveals that [HS3ST3A1](/details-gene/9955) shows highly significant expression in specialized cells of the nervous system, particularly retinal cells such as the `[H2 horizontal cell](/details-cell/CL0004218)` and `[H1 horizontal cell](/details-cell/CL0004217)`, as well as in various mesenchymal-derived cell types like fibroblasts and chondrocytes. This expression pattern suggests a role in neural development, retinal function, and extracellular matrix biology. Notably, the specific 3-O-sulfated heparan sulfate structures generated by this enzyme have been identified as essential entry receptors for Herpes Simplex Virus 1 (HSV-1) ([Link](https://doi.org/10.1016/s0092-8674(00)80058-6)). ## Cellular Roles and Expression Landscape The expression profile of [HS3ST3A1](/details-gene/9955) points to a specialized role in a distinct subset of neural and structural cell types. **Overall**, its most significant expression is observed within the retina, with top markers being `[H2 horizontal cell](/details-cell/CL0004218)` (CSI: 6.45) and `[H1 horizontal cell](/details-cell/CL0004217)` (CSI: 3.95), along with `[Mueller cell](/details-cell/CL0000636)` (CSI: 3.02). This strong retinal signature suggests a critical function in the development, maintenance, or signaling processes of the neural retina. Beyond the retina, [HS3ST3A1](/details-gene/9955) is significantly expressed in other cells of the broader nervous system and its supporting structures, including `[neural crest cell](/details-cell/CL0011012)`, `[ependymal cell](/details-cell/CL0000065)`, `[choroid plexus epithelial cell](/details-cell/CL0000706)`, and `[Schwann cell](/details-cell/CL0002573)`. This indicates a widespread involvement in modifying the heparan sulfate proteoglycans in the extracellular environment of the central and peripheral nervous systems. A secondary but significant expression pattern is evident in mesenchymal and connective tissue cells. This includes high significance in `[fibroblast of lung](/details-cell/CL0002553)`, `[hepatic stellate cell](/details-cell/CL0000632)`, and `[chondrocyte](/details-cell/CL0000138)`. This pattern suggests that the specific 3-O-sulfated HS structures it generates are also important components of the extracellular matrix in non-neural tissues, potentially regulating growth factor binding, tissue repair, or fibrosis. The absence of hematopoietic or lymphoid cells from the top expression list suggests a highly specific role outside of the typical immune system. ## Pathways and Molecular Function The function of [HS3ST3A1](/details-gene/9955) is centered on the post-translational modification of proteoglycans. As annotated by the Gene Ontology, its molecular function is `[sulfotransferase activity](/details-go/GO:0008146)`, specifically `[[heparan sulfate]-glucosamine 3-sulfotransferase 3 activity](/details-go/GO:0033872)`. This enzymatic activity occurs within the `[Golgi membrane](/details-go/GO:0000139)`, where it participates in the `[heparan sulfate proteoglycan biosynthetic process, enzymatic modification](/details-go/GO:0015015)`. These molecular activities are integral to several broader biological pathways. According to Reactome, [HS3ST3A1](/details-gene/9955) is a key player in `[Glycosaminoglycan metabolism](/details-reactome/R-HSA-1630316)`, and more specifically, `[Hs-gag biosynthesis](/details-reactome/R-HSA-2022928)`. The heparan sulfate chains it modifies are essential for a wide range of biological processes, including cell adhesion, growth factor signaling, and morphogenesis, as reflected in its association with `[Branching involved in ureteric bud morphogenesis](/details-go/GO:0001658)`. The specific 3-O-sulfated structures created by [HS3ST3A1](/details-gene/9955) can dramatically alter the binding properties of heparan sulfate, enabling high-affinity interactions with specific ligands, including viral glycoproteins ([Link](https://doi.org/10.1074/jbc.m405013200)). ## Research Directions The specific role of [HS3ST3A1](/details-gene/9955) in creating a cellular entry receptor for HSV-1, combined with its highly specific expression pattern, opens several avenues for future research. The enzyme's product directly facilitates pathogenesis, making its regulation and cell-type specificity a critical area of investigation. Based on the available data, several testable hypotheses can be proposed: 1. The highly restricted expression of [HS3ST3A1](/details-gene/9955) in specific neuronal subtypes, such as retinal horizontal cells and Schwann cells, dictates the cellular tropism and latency sites of Herpes Simplex Virus 1 within the nervous system. 2. In non-neural tissues like the lung and liver, the expression of [HS3ST3A1](/details-gene/9955) in fibroblasts and stellate cells contributes to pathological fibrosis by generating specific heparan sulfate structures that enhance signaling pathways (e.g., TGF-β or FGF) involved in extracellular matrix deposition. 3. The enzyme's activity is a rate-limiting step in generating the specific 3-O-sulfated heparan sulfate ligand required for certain developmental signaling pathways, and its misregulation could contribute to congenital abnormalities in neural or renal development. To investigate the first and most clinically relevant hypothesis, a key experiment would be to determine if [HS3ST3A1](/details-gene/9955) is necessary for HSV-1 entry into relevant cell types. To test this, one could utilize CRISPR-Cas9 to knock out [HS3ST3A1](/details-gene/9955) in a susceptible human cell line, such as retinal pigment epithelial cells (ARPE-19) or a neuroblastoma line (SH-SY5Y). The infectivity of HSV-1 in these knockout cells would then be compared to wild-type controls using plaque assays or by quantifying viral gene expression via RT-qPCR. This would directly assess if the absence of [HS3ST3A1](/details-gene/9955) confers resistance to infection. Given its role in facilitating viral entry, [HS3ST3A1](/details-gene/9955) represents an attractive host-directed therapeutic target. **Inhibition** of its sulfotransferase activity, rather than activation, would be the therapeutic goal. Developing small molecule inhibitors that specifically block the active site of the enzyme could serve as a novel antiviral strategy, preventing HSV-1 from binding to and entering host cells. Such a host-targeted approach might be less susceptible to the development of viral resistance compared to traditional antivirals that target viral proteins.

Genular Protein ID: 3602497980

Symbol: HS3SA_HUMAN

Name: Heparan sulfate glucosamine 3-O-sulfotransferase 3A1

UniProtKB Accession Codes:

Q9Y663 A8K7N2

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 9 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 EC 1 EMBL 5 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 8 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 4 PDBsum 4 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 3 SMR 1 STRING 1 SUPFAM 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9988767

Title: Multiple isoforms of heparan sulfate D-glucosaminyl 3-O-sulfotransferase. Isolation, characterization, and expression of human cDNAs and identification of distinct genomic loci.

PubMed ID: 9988767

DOI: 10.1074/jbc.274.8.5170

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 10520990

Title: A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry.

PubMed ID: 10520990

DOI: 10.1016/s0092-8674(00)80058-6

PubMed ID: 9988768

Title: Expression of heparan sulfate D-glucosaminyl 3-O-sulfotransferase isoforms reveals novel substrate specificities.

PubMed ID: 9988768

DOI: 10.1074/jbc.274.8.5185

PubMed ID: 10608887

Title: Heparan sulfate D-glucosaminyl 3-O-sulfotransferase-3A sulfates N-unsubstituted glucosamine residues.

PubMed ID: 10608887

DOI: 10.1074/jbc.274.53.38155

PubMed ID: 15304505

Title: Structural analysis of the sulfotransferase (3-o-sulfotransferase isoform 3) involved in the biosynthesis of an entry receptor for herpes simplex virus 1.

PubMed ID: 15304505

DOI: 10.1074/jbc.m405013200

Sequence Information:

  • Length: 406
  • Mass: 44900
  • Checksum: 57B6A0ABC897577A
  • Sequence:
    • MAPPGPASAL STSAEPLSRS IFRKFLLMLC SLLTSLYVFY CLAERCQTLS GPVVGLSGGG 
EEAGAPGGGV LAGGPRELAV WPAAAQRKRL LQLPQWRRRR PPAPRDDGEE AAWEEESPGL 
SGGPGGSGAG STVAEAPPGT LALLLDEGSK QLPQAIIIGV KKGGTRALLE FLRVHPDVRA 
VGAEPHFFDR SYDKGLAWYR DLMPRTLDGQ ITMEKTPSYF VTREAPARIS AMSKDTKLIV 
VVRDPVTRAI SDYTQTLSKR PDIPTFESLT FKNRTAGLID TSWSAIQIGI YAKHLEHWLR 
HFPIRQMLFV SGERLISDPA GELGRVQDFL GLKRIITDKH FYFNKTKGFP CLKKAEGSSR 
PHCLGKTKGR THPEIDREVV RRLREFYRPF NLKFYQMTGH DFGWDG