OTUD3 — OTU Deubiquitinase 3

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OTUD3 — OTU Deubiquitinase 3

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OTUD3 — OTU Deubiquitinase 3

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">OTUD3 — OTU Deubiquitinase 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>OTUD3</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>OTU Deubiquitinase 3</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>17p13.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/57567" target="_blank">57567</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000167695" target="_blank">ENSG00000167695</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/607375" target="_blank">607375</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q5T7Q2" target="_blank">Q5T7Q2</a></td>
</tr>
<tr>
<td class="label">PARK Locus</td>
<td>PARK11</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/parkinsons-disease">Parkinson's Disease</a></td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain, Heart, Kidney, Liver</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color

...

OTUD3 — OTU Deubiquitinase 3

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">OTUD3 — OTU Deubiquitinase 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>OTUD3</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>OTU Deubiquitinase 3</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>17p13.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/57567" target="_blank">57567</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000167695" target="_blank">ENSG00000167695</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/607375" target="_blank">607375</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q5T7Q2" target="_blank">Q5T7Q2</a></td>
</tr>
<tr>
<td class="label">PARK Locus</td>
<td>PARK11</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td><a href="/diseases/parkinsons-disease">Parkinson's Disease</a></td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain, Heart, Kidney, Liver</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">13 edges</a></td>
</tr>
</table>

OTUD3 — OTU Deubiquitinase 3

Overview

Mermaid diagram (expand to render)

OTUD3 (OTU Deubiquitinase 3), encoded by the OTUD3 gene on chromosome 17p13.1, is a member of the ovarian tumor (OTU) family of deubiquitinating enzymes. The gene has been implicated in Parkinson's disease (PD) as a potential causative gene for PARK11, though the pathogenicity of OTUD3 variants remains controversial and uncertain.

Introduction

OTUD3 was first linked to Parkinson's disease in 2014 when whole-exome sequencing studies identified rare variants in patients with familial PD[@yang2014][@shi2014]. However, subsequent studies have yielded conflicting results regarding the pathogenic nature of OTUD3 variants, and its role in PD pathogenesis remains uncertain compared to established PD genes like [LRRK2](/genes/lrrk2) or [SNCA](/genes/snca).

The OTUD3 protein functions as a deubiquitinase (DUB), an enzyme that removes ubiquitin chains from target proteins, thereby regulating protein stability, signaling pathways, and cellular homeostasis.

Structure

OTUD3 is a 524-amino acid protein with the following domain architecture:

OTU Domain (Residues 85-270)

The core catalytic domain shares homology with other OTU family deubiquitinases:

Catalytic triad: Cys-His-Asp residues required for protease activity
Ubiquitin-binding surface: Interacts with ubiquitin substrates
zinc-finger motif: Stabilizes the domain structure

N-Terminal Region (Residues 1-84)

Contains low-complexity sequences
May mediate protein-protein interactions

C-Terminal Region (Residues 271-524)

Regulatory functions
Potential interaction motifs

Normal Function

Under physiological conditions, OTUD3 participates in several cellular processes:

Deubiquitination Activity

OTUD3 removes ubiquitin chains from target proteins:

K48-linked chains: Typically target proteins for proteasomal degradation
K63-linked chains: Regulate signaling complexes and endocytosis
Linear chains: Regulate NF-κB signaling pathways

Cellular Pathways

p53 pathway: OTUD3 can stabilize p53 by removing ubiquitination
AKT signaling: Regulates AKT protein stability and signaling
Cellular stress response: Involved in DNA damage repair
Protein quality control: Maintains cellular proteostasis

Tissue Distribution

OTUD3 is expressed in multiple tissues:

Brain: Neurons and glial cells
Heart: Cardiac myocytes
Kidney: Renal tubular cells
Liver: Hepatocytes

Parkinson's Disease Association

Evidence for Pathogenic Role

The initial studies linking OTUD3 to PD reported:

Rare missense variants in familial PD patients

Loss-of-function variants that reduce deubiquitinase activity

Functional studies showing impaired mitophagy regulation

Controversy and Uncertainties

Subsequent investigations have raised questions about OTUD3's pathogenicity:

Limited segregation in affected families

Variable frequency in different populations

Lack of definitive functional validation in animal models

No robust replication in large cohort studies

Compared to established PD genes such as [LRRK2](/genes/lrrk2), [GBA](/genes/gba), or [SNCA](/genes/snca), OTUD3 remains a gene of uncertain significance in PD genetics.

Current Classification

PARK11 status: Considered uncertain/controversial
ACMG classification: Variants typically classified as variants of uncertain significance (VUS)
Clinical utility: Not currently used for clinical testing

Therapeutic Implications

Given the uncertain pathogenicity of OTUD3 variants, therapeutic targeting remains speculative:

Potential Therapeutic Approaches

Deubiquitinase modulation: If OTUD3 loss-of-function contributes to PD, activating compounds could be beneficial

Protein stabilization: Enhancing OTUD3 expression or activity

下游 pathways: Targeting downstream effectors of OTUD3 deubiquitinase activity

Research Directions

Better understanding of OTUD3 substrate specificity
Development of cellular and animal models
Correlation with clinical phenotypes

OTUD3 interacts with several PD-relevant pathways:

[LRRK2](/genes/lrrk2): Both implicated in PD, though LRRK2 has stronger evidence
[GBA](/genes/gba): Established PD gene involved in autophagy
[SNCA](/genes/snca): Alpha-synuclein aggregation pathway
[Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system): Core pathway for protein clearance
[Mitophagy](/mechanisms/mitophagy-pathway): Mitochondrial quality control

References

[Sharif et al., OTUD3 deubiquitinase activity (2023)](https://doi.org/10.1016/j.jbc.2023.104928)

[Yang et al., OTUD3 suppresses Parkinson's disease pathogenesis (2014)](https://doi.org/10.1038/nn.3638)

[Shi et al., OTUD3 variants in patients with Parkinson's disease (2014)](https://doi.org/10.1001/jamaneurol.2014.1065)

[Miron et al., Structural basis for OTUD proteins (2018)](https://doi.org/10.1038/s41467-018-04150-7)

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Related Entities

OTUD3

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-otud3
kg_node_id	OTUD3
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5e3d72369961
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-otud3'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

15%

Debates

0

Incoming

3

Outgoing

16

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

OTUD3 — OTU Deubiquitinase 3

OTUD3 — OTU Deubiquitinase 3

OTUD3 — OTU Deubiquitinase 3

OTUD3 — OTU Deubiquitinase 3

Overview

Introduction

Structure

OTU Domain (Residues 85-270)

N-Terminal Region (Residues 1-84)

C-Terminal Region (Residues 271-524)

Normal Function

Deubiquitination Activity

Cellular Pathways

Tissue Distribution

Parkinson's Disease Association

Evidence for Pathogenic Role

Controversy and Uncertainties

Current Classification

Therapeutic Implications

Potential Therapeutic Approaches

Research Directions

References

💬 Discussion

📗 Cite This Artifact

OTUD3 — OTU Deubiquitinase 3

OTUD3 — OTU Deubiquitinase 3

OTUD3 — OTU Deubiquitinase 3

OTUD3 — OTU Deubiquitinase 3

Overview

Introduction

Structure

OTU Domain (Residues 85-270)

N-Terminal Region (Residues 1-84)

C-Terminal Region (Residues 271-524)

Normal Function

Deubiquitination Activity

Cellular Pathways

Tissue Distribution

Parkinson's Disease Association

Evidence for Pathogenic Role

Controversy and Uncertainties

Current Classification

Therapeutic Implications

Potential Therapeutic Approaches

Research Directions

Related Genes and Pathways

References

💬 Discussion