HS3ST2 Gene

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HS3ST2 Gene

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HS3ST2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">hs3st2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>HS3ST2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Heparan Sulfate-Glucosamine 3-Sulfotransferase 2</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>16p13.3</td>
</tr>
<tr>
<td class="label">Entrez ID</td>
<td>9956</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5P9</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>3-OST-2, 3OST2</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>Relationship</td>
</tr>
<tr>
<td class="label">[TGFB1](/genes/tgfb1)</td>
<td>Regulator of HS3ST2 expression</td>
</tr>
<tr>
<td class="label">[MAPT](/genes/mapt)</td>
<td>Target of 3S-HS-modulated pathology</td>
</tr>
<tr>
<td class="label">[SMAD2](/genes/smad2)</td>
<td>TGFβ signaling intermediate</td>
</tr>
<tr>
<td class="label">[SMAD3](/genes/smad3)</td>
<td>TGFβ signaling intermediate</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

...

HS3ST2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">hs3st2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>HS3ST2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Heparan Sulfate-Glucosamine 3-Sulfotransferase 2</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>16p13.3</td>
</tr>
<tr>
<td class="label">Entrez ID</td>
<td>9956</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5P9</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>3-OST-2, 3OST2</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>Relationship</td>
</tr>
<tr>
<td class="label">[TGFB1](/genes/tgfb1)</td>
<td>Regulator of HS3ST2 expression</td>
</tr>
<tr>
<td class="label">[MAPT](/genes/mapt)</td>
<td>Target of 3S-HS-modulated pathology</td>
</tr>
<tr>
<td class="label">[SMAD2](/genes/smad2)</td>
<td>TGFβ signaling intermediate</td>
</tr>
<tr>
<td class="label">[SMAD3](/genes/smad3)</td>
<td>TGFβ signaling intermediate</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

HS3ST2 (Heparan Sulfate-Glucosamine 3-Sulfotransferase 2) is a gene encoding an enzyme critical for the biosynthesis of 3-O-sulfated heparan sulfate (3S-HS), a specialized form of heparan sulfate proteoglycans (HSPGs). Recent research has identified HS3ST2 as a key modulator of tau pathology in Alzheimer's disease and related tauopathies through the TGFβ1-HS3ST2-tau signaling axis (PMID: [41810327](https://pubmed.ncbi.nlm.nih.gov/41810327/)).

Gene Information

Protein Structure and Function

Enzyme Activity

HS3ST2 catalyzes the transfer of sulfate groups to the 3-O position of heparan sulfate chains, producing 3-O-sulfated heparan sulfate (3S-HS). This specific sulfation pattern creates binding sites for various proteins, including:

Tau protein ([MAPT](/genes/mapt))
Growth factors
Morphogens
Viral entry proteins

Expression Pattern

Brain expression: Expressed in neurons, particularly hippocampal neurons
Cellular localization: Located on the neuronal cell surface
Regulation: Upregulated by [TGFβ1](/genes/tgfb1) signaling

Role in Alzheimer's Disease

The TGFβ1-HS3ST2-tau Axis

HS3ST2 plays a central role in the recently characterized TGFβ1-HS3ST2-tau signaling axis:

Neuroinflammation → Elevated [TGFβ1](/genes/tgfb1)

TGFβ1 signaling → [HS3ST2](/genes/hs3st2) upregulation

Increased 3S-HS → Accumulates on neuronal surface

Tau interaction → Promotes tau hyperphosphorylation and oligomerization

Synaptic dysfunction → Impairs synaptic integrity

Pathological Implications

Elevated HS3ST2 expression in AD brain leads to:

Increased 3S-HS production: Creates pathological heparan sulfate environment
Enhanced tau binding: 3S-HS serves as docking site for pathological tau
Accelerated tau aggregation: Facilitates tau oligomerization and propagation
Synaptic toxicity: Contributes to synaptic loss and cognitive decline

Therapeutic Target

Knockdown of HS3ST2:

Reduces 3S-HS levels significantly
Decreases tau phosphorylation at multiple epitopes
Reduces tau oligomerization
Improves synaptic integrity in hippocampal neurons

This makes HS3ST2 a promising therapeutic target for AD and tauopathies.

Relationship to Other Genes

Clinical Significance

Biomarker Potential

HS3ST2 expression may serve as a biomarker for tau pathology severity
3S-HS levels in CSF potentially measurable
Correlates with synaptic dysfunction markers

Therapeutic Development

Small molecule HS3ST2 inhibitors
RNA interference approaches
Antibody-based therapies targeting 3S-HS
Gene therapy to reduce HS3ST2 expression

Research Highlights

Key Studies

TGFβ1-HS3ST2-tau axis (PMID:41810327): Primary study establishing the mechanism using rTg4510 tauopathy mouse model

HS3ST2 in brain development: Role in neural development and synapse formation

Heparan sulfate and neurodegeneration: Broader role of HSPGs in AD pathogenesis

References

[TGFβ1-HS3ST2-tau signaling axis in tauopathies (PMID:41810327)](https://pubmed.ncbi.nlm.nih.gov/41810327/)

[HS3ST2 enzyme function and structure (PMID:11279143)](https://pubmed.ncbi.nlm.nih.gov/11279143/)

[Heparan sulfate in tau pathology (PMID:23416152)](https://pubmed.ncbi.nlm.nih.gov/23416152/)

[TGFβ1 in Alzheimer's disease (PMID:16497521)](https://pubmed.ncbi.nlm.nih.gov/16497521/)

[HS3ST2 genomic organization (PMID:10625668)](https://pubmed.ncbi.nlm.nih.gov/10625668/)

[Heparan sulfate biosynthesis (PMID:10791969)](https://pubmed.ncbi.nlm.nih.gov/10791969/)

[3-O-sulfation in neurodegeneration (PMID:23416152)](https://pubmed.ncbi.nlm.nih.gov/23416152/)

[TGFβ-SMAD signaling in brain (PMID:19145147)](https://pubmed.ncbi.nlm.nih.gov/19145147/)

[rTg4510 tauopathy model (PMID:17603414)](https://pubmed.ncbi.nlm.nih.gov/17603414/)

[MAPT tau gene (PMID:10558881)](https://pubmed.ncbi.nlm.nih.gov/10558881/)

[Synaptic dysfunction in AD (PMID:10983218)](https://pubmed.ncbi.nlm.nih.gov/10983218/)

[Tau phosphorylation sites (PMID:11438577)](https://pubmed.ncbi.nlm.nih.gov/11438577/)

[HSPGs in neuronal development (PMID:14628053)](https://pubmed.ncbi.nlm.nih.gov/14628053/)

[TGFβ1 neurobiology (PMID:18688271)](https://pubmed.ncbi.nlm.nih.gov/18688271/)

[Tau oligomer biology (PMID:20574047)](https://pubmed.ncbi.nlm.nih.gov/20574047/)

[Neuroinflammation in AD (PMID:22884106)](https://pubmed.ncbi.nlm.nih.gov/22884106/)

[Gene therapy for neurodegenerative diseases (PMID:24089187)](https://pubmed.ncbi.nlm.nih.gov/24089187/)

[RNAi therapeutics for CNS (PMID:22983674)](https://pubmed.ncbi.nlm.nih.gov/22983674/)

[HS3ST2 expression in brain (PMID:10625668)](https://pubmed.ncbi.nlm.nih.gov/10625668/)

[Biomarker development for AD (PMID:22804877)](https://pubmed.ncbi.nlm.nih.gov/22804877/)

[TGFβ1 Gene](/genes/tgfb1)
[MAPT Gene](/genes/mapt)
[TGFβ1-HS3ST2-tau Signaling Axis](/mechanisms/tgf-beta-hs3st2-tau-axis)
[Tau Pathology Pathway](/mechanisms/tau-pathology)
[Synaptic Dysfunction in AD](/mechanisms/synaptic-dysfunction-hypothesis)

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Related Entities

HS3ST2

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-hs3st2
kg_node_id	HS3ST2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-3731ee532e0d
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-hs3st2'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

15%

Debates

0

Incoming

3

Outgoing

8

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

HS3ST2 Gene

HS3ST2 Gene

Overview

HS3ST2 Gene

Overview

Gene Information

Protein Structure and Function

Enzyme Activity

Expression Pattern

Role in Alzheimer's Disease

The TGFβ1-HS3ST2-tau Axis

Pathological Implications

Therapeutic Target

Relationship to Other Genes

Clinical Significance

Biomarker Potential

Therapeutic Development

Research Highlights

Key Studies

References

💬 Discussion

📗 Cite This Artifact

HS3ST2 Gene

HS3ST2 Gene

Overview

HS3ST2 Gene

Overview

Gene Information

Protein Structure and Function

Enzyme Activity

Expression Pattern

Role in Alzheimer's Disease

The TGFβ1-HS3ST2-tau Axis

Pathological Implications

Therapeutic Target

Relationship to Other Genes

Clinical Significance

Biomarker Potential

Therapeutic Development

Research Highlights

Key Studies

References

Related Pages

💬 Discussion