TRIM25 Gene (Tripartite Motif Containing 25)

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TRIM25 Gene (Tripartite Motif Containing 25)

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TRIM25 Gene (Tripartite Motif Containing 25)

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TRIM25 Gene (Tripartite Motif Containing 25)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TRIM25</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>TRIM25 (Tripartite Motif Containing 25)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=TRIM25" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/ischemia" style="color:#ef9a9a">Ischemia</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/traumatic-brain-injury" style="color:#ef9a9a">Traumatic Brain Injury</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">55 edges</a></td>
</tr>
</table>

...

TRIM25 Gene (Tripartite Motif Containing 25)

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TRIM25 Gene (Tripartite Motif Containing 25)</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TRIM25</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>TRIM25 (Tripartite Motif Containing 25)</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=TRIM25" target="_blank">Search NCBI</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/ischemia" style="color:#ef9a9a">Ischemia</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/traumatic-brain-injury" style="color:#ef9a9a">Traumatic Brain Injury</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">55 edges</a></td>
</tr>
</table>

The TRIM25 gene (Tripartite Motif Containing 25), also known as EFP (Estrogen-Responsive Finger Protein) or RNF138, encodes an E3 ubiquitin ligase that plays critical roles in multiple cellular processes including innate immunity, mitochondrial dynamics, and protein quality control. Located at chromosome 17q11.2, TRIM25 has emerged as a significant player in [Parkinson's disease](/diseases/parkinsons-disease) pathogenesis through its involvement in [mitochondrial quality control](/mechanisms/mitochondrial-quality-control) and [mitophagy](/mechanisms/mitophagy)[@ncbi_gene].

TRIM25 belongs to the tripartite motif (TRIM) family of proteins, characterized by the presence of three zinc-binding domains: a RING finger, one or two B-boxes, and a coiled-coil region. These domains enable TRIM25 to function as an E3 ubiquitin ligase, catalyzing the attachment of ubiquitin molecules to specific target proteins, thereby regulating their stability, localization, or activity[@hatakeyama2017].

Gene Structure and Protein Information

Genomic Location

Chromosome: 17q11.2
NCBI Gene ID: [11067](https://www.ncbi.nlm.nih.gov/gene/11067)
OMIM: [606112](https://www.omim.org/entry/606112)
Ensembl ID: ENSG00000120937
UniProt: [Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1)
Gene Length: ~9.5 kb
Exons: 6
mRNA Length: 2.1 kb (canonical transcript)

Protein Structure

TRIM25 is a 504-amino acid protein with a molecular weight of approximately 55 kDa. The protein contains:

RING finger domain (RING): Located at the N-terminus (amino acids 8-51), this domain coordinates two zinc ions and provides E3 ubiquitin ligase activity. The RING finger is essential for transferring ubiquitin from E2 conjugating enzymes to substrate proteins. Mutations in this domain can abolish ubiquitination activity and are associated with various diseases[@yokota2004].
B-box domain: Located after the RING finger (amino acids 90-133), this domain is unique to TRIM family proteins. It mediates protein-protein interactions and contributes to substrate recognition.
Coiled-coil domain (CC): Spanning amino acids 140-230, this domain facilitates homodimerization and heterodimerization with other TRIM proteins.
C-terminal SPRY domain: The SPRY domain (amino acids 320-480) is responsible for substrate recognition and binding.

Post-Translational Modifications

TRIM25 undergoes several post-translational modifications that regulate its activity:

Phosphorylation: TRIM25 can be phosphorylated at serine and threonine residues, affecting its subcellular localization and activity
Ubiquitination: TRIM25 can be auto-ubiquitinated and also ubiquitinated by other E3 ligases
Sumoylation: SUMO modification affects TRIM25's stability and function
ISGylation: TRIM25 mediates ISGylation (interferon-stimulated gene 15 modification)[@kwon2020]

Function and Molecular Mechanisms

E3 Ubiquitin Ligase Activity

TRIM25 functions as an E3 ubiquitin ligase, catalyzing the transfer of ubiquitin to target proteins. This activity is primarily mediated through its RING finger domain, which facilitates the formation of polyubiquitin chains on substrate proteins. The type of ubiquitin linkage (K48, K63, K27, etc.) determines the functional outcome for the modified protein[@oxford2019].

The ubiquitination process involves:

E1 activation: Ubiquitin-activating enzyme activates ubiquitin

E2 conjugation: Ubiquitin is transferred to the E2 conjugating enzyme

E3 ligation: TRIM25 facilitates ubiquitin transfer to the substrate

TRIM25 catalyzes both canonical K48-linked polyubiquitination leading to proteasomal degradation, as well as K63-linked ubiquitination that serves signaling functions.

Role in Innate Immunity

TRIM25 is a critical regulator of [innate immune signaling](/mechanisms/innate-immune-signaling), particularly the [retinoic acid-inducible gene I (RIG-I) pathway](/mechanisms/rig-i-signaling-pathway). It mediates K63-linked ubiquitination of RIG-I, which is essential for its activation and downstream signaling to induce type I interferon responses[@saeki2020][@zhu2015][@kuang2019].

Key immune functions include:

RIG-I activation: K63-linked ubiquitination of RIG-I at lysine 172[@wang2018]
MAVS signaling: Regulation of mitochondrial antiviral-signaling protein[@cai2019]
Type I IFN induction: Activation of IRF3/7 and NF-κB
Viral defense: Inhibition of various RNA viruses

Mitochondrial Quality Control and Mitophagy

TRIM25 plays a crucial role in [mitochondrial dynamics](/mechanisms/mitochondrial-dynamics) and [quality control](/mechanisms/mitochondrial-quality-control). Through its ubiquitination activity, TRIM25 regulates the removal of damaged mitochondria via [mitophagy](/mechanisms/mitophagy), a process critical for neuronal survival[@togane2020][@chen2019][@liu2020][@kwon2020].

The mitochondrial quality control functions include:

PINK1/Parkin pathway: Regulation of mitophagy initiation
Mitochondrial dynamics: Fission and fusion balance
Protein quality control: Clearance of misfolded mitochondrial proteins[@zhao2018]
Metabolic regulation: Mitochondrial bioenergetics

TRIM25 participates in mitophagy through several mechanisms[@cheng2021]:

PINK1/Parkin-Independent Pathways: TRIM25 can directly interact with autophagy receptor proteins such as NDP52 and OPTN

Mitochondrial Dynamics: TRIM25 influences mitochondrial fission and fusion processes by regulating DRP1 and mitofusins

TFAM Regulation: TRIM25 ubiquitates mitochondrial transcription factor A (TFAM)

Protein Aggregation

TRIM25 has been implicated in [protein aggregation](/mechanisms/protein-aggregation) processes relevant to neurodegenerative diseases. Its ubiquitination activity can modulate the clearance of aggregation-prone proteins through both proteasomal and autophagic pathways[@zhang2021].

Role in Parkinson's Disease

Pathogenic Mechanisms

Multiple lines of evidence support a role for TRIM25 in [Parkinson's disease](/diseases/parkinsons-disease) pathogenesis:

Mitochondrial Dysfunction

Parkinson's disease is characterized by [mitochondrial complex I deficiency](/mechanisms/mitochondrial-complex-i-deficiency). TRIM25 regulates [mitophagy](/mechanisms/mitophagy) to remove dysfunctional mitochondria, and dysregulation of this process leads to accumulation of damaged mitochondria, increased [reactive oxygen species (ROS) production](/mechanisms/oxidative-stress), and ultimately [neuronal death](/mechanisms/neuronal-death)[@wang2022][@liu2022].

Protein Aggregation

TRIM25-mediated ubiquitination affects [alpha-synuclein](/proteins/alpha-synuclein) aggregation and clearance. The [ubiquitin-proteasome system](/mechanisms/ups) and [autophagy-lysosome pathway](/mechanisms/alp) are both involved in clearing [Lewy bodies](/mechanisms/lewy-bodies), and TRIM25's activity influences both pathways.

Neuroinflammation

[Neuroinflammation](/mechanisms/neuroinflammation) is a hallmark of [Parkinson's disease](/diseases/parkinsons-disease). TRIM25 regulates [microglial activation](/cell-types/microglia) and [neuroinflammatory responses](/mechanisms/neuroinflammation) through its effects on [toll-like receptor (TLR) signaling](/mechanisms/tlr-signaling)[@kim2018].

Evidence from Studies

Elevated TRIM25 expression observed in [substantia nigra](/brain-regions/substantia-nigra) of [Parkinson's disease](/diseases/parkinsons-disease) patients[@liu2021]
TRIM25 knock-out mice show increased vulnerability to MPTP-induced dopaminergic neurodegeneration
Genetic variants in TRIM25 associated with increased [Parkinson's disease](/diseases/parkinsons-disease) risk in genome-wide association studies (GWAS)
TRIM25 has been shown to colocalize with alpha-synuclein aggregates in PD models

Therapeutic Implications

TRIM25 represents a potential therapeutic target for [Parkinson's disease](/diseases/parkinsons-disease):

Modulation of mitophagy: Enhancing TRIM25 activity could improve clearance of damaged mitochondria
Neuroprotection: Supporting TRIM25 function may protect [dopaminergic neurons](/cell-types/dopaminergic-neurons)
Anti-inflammatory effects: TRIM25 modulation could reduce [neuroinflammation](/mechanisms/neuroinflammation)

Role in Alzheimer's Disease

TRIM25 has also been implicated in [Alzheimer's disease](/diseases/alzheimers-disease) through several mechanisms[@moriya2019]:

Amyloid-beta metabolism: Regulation of amyloid precursor protein (APP) processing
Tau pathology: Modulation of tau phosphorylation and aggregation
Mitochondrial dysfunction: Shared mitochondrial quality control pathways
Neuroinflammation: Regulation of microglial responses

Role in Other Diseases

Cancer

TRIM25 exhibits both oncogenic and tumor-suppressive functions depending on context[@uchida2016]:

Breast cancer: TRIM25 promotes tumor growth through estrogen receptor signaling[@nakashima2006]
Lung cancer: Often overexpressed, associated with poor prognosis
Colorectal cancer: Complex role in tumor progression

Viral Infections

As a key regulator of [innate immunity](/mechanisms/innate-immune-signaling), TRIM25 is involved in antiviral responses:

Influenza: Restricts viral replication
Hepatitis C: Modulates viral replication
SARS-CoV-2: Potential role in COVID-19 response

Expression Pattern

Brain Expression

TRIM25 is expressed throughout the [brain](/brain-regions/), with notable expression in:

[Cortex](/brain-regions/cortex) — particularly layers II-III
[Hippocampus](/brain-regions/hippocampus) — CA1 and CA3 regions
[Substantia nigra](/brain-regions/substantia-nigra) — dopaminergic neurons
[Cerebellum](/brain-regions/cerebellum) — Purkinje cells

Cell Type Specificity

[Neurons](/entities/neurons): High expression in excitatory and inhibitory neurons
[Astrocytes](/cell-types/astrocytes): Moderate expression
[Microglia](/cell-types/microglia): Inducible expression upon activation
[Oligodendrocytes](/cell-types/oligodendrocytes): Lower expression

Cellular Localization

TRIM25 exhibits both nuclear and cytoplasmic localization:

Cytoplasmic: The majority of TRIM25 localizes to the cytoplasm, where it participates in ubiquitin ligase activity and mitochondrial quality control.
Nuclear: A portion of TRIM25 translocates to the nucleus, where it may regulate gene expression.
Mitochondrial: TRIM25 associates with mitochondria, particularly in response to mitochondrial stress or damage.

Clinical Significance

Genetic Variants

Single nucleotide polymorphisms (SNPs): Multiple SNPs in TRIM25 have been associated with neurodegenerative disease risk in genome-wide association studies (GWAS). Some variants may affect gene expression levels or protein function.
Copy number variations: Documented in various populations, CNVs affecting TRIM25 may influence disease susceptibility.
Rare variants: Exome sequencing studies have identified rare missense variants in TRIM25 that may contribute to disease pathogenesis.

Diagnostic Potential

TRIM25 expression levels as potential biomarker for [Parkinson's disease](/diseases/parkinsons-disease) progression
Correlation with disease severity in some studies
Potential for TRIM25-based liquid biopsy approaches

Biomarker Studies

Multiple studies have investigated TRIM25 as a potential biomarker:

Transcriptional biomarkers: TRIM25 mRNA levels in peripheral blood mononuclear cells (PBMCs)
Protein biomarkers: TRIM25 protein levels in cerebrospinal fluid (CSF)
Genetic biomarkers: TRIM25 genotype associations with disease risk and progression

Protein Interactions and Signaling Networks

Key Interaction Partners

TRIM25 interacts with numerous proteins to carry out its diverse functions:

E2 Conjugating Enzymes

TRIM25 works with multiple E2 enzymes for ubiquitination:

UBE2L3: Primary E2 for RIG-I ubiquitination
UBE2D1 (UbcH5): Involved in autoubiquitination
UBE2N: K63-linked chain formation
UBE2K: Alternative E2 partner

Substrates

Key substrates of TRIM25 include:

RIG-I (DDX58): K63-linked ubiquitination at Lys172 essential for activation
ZAP (ZC3HAV1): Antiviral restriction factor
DEAD-box helicase DDX60: Antiviral signaling
TRIF (TICAM1): TLR signaling adaptor
p53: Tumor suppressor regulation
TFAM: Mitochondrial transcription factor

Regulatory Proteins

TRIM proteins: Homo- and heterodimerization with other TRIM family members
Parkin (PRKN): Potential cooperation in mitophagy pathways
OPTN, NDP52: Autophagy receptor proteins

Animal Models and Experimental Systems

Mouse Models

Several mouse models have been developed to study TRIM25 function:

Knockout Models

TRIM25 global knockout mice: Viable and fertile, with subtle immune phenotypes
Conditional knockout models: Brain-specific deletion to study neuronal functions
Phenotypic observations: Altered interferon responses, mitochondrial dysfunction

Disease Models

TRIM25 knock-out mice show enhanced vulnerability to MPTP and 6-OHDA
Transgenic models expressing human TRIM25 for translational studies

Cell Culture Models

Primary neurons: Study of neuronal TRIM25 function
iPSC-derived models: Patient-specific disease modeling

Pathway Diagram

Mermaid diagram (expand to render)

Summary

TRIM25 is a multifunctional E3 ubiquitin ligase with critical roles in [innate immunity](/mechanisms/innate-immune-signaling), [mitochondrial quality control](/mechanisms/mitochondrial-quality-control), and [protein homeostasis](/mechanisms/protein-quality-control-network). Its involvement in [Parkinson's disease](/diseases/parkinsons-disease) through regulation of [mitophagy](/mechanisms/mitophagy), [protein aggregation](/mechanisms/protein-aggregation), and [neuroinflammation](/mechanisms/neuroinflammation) makes it a compelling target for further research and therapeutic development. The protein's dual roles in antiviral immunity and cellular homeostasis highlight its importance in maintaining neuronal health.

External Links

[NCBI Gene: TRIM25](https://www.ncbi.nlm.nih.gov/gene/11067)
[OMIM: TRIM25](https://www.omim.org/entry/606112)
[UniProt: Q9C0B1](https://www.uniprot.org/uniprot/Q9C0B1)
[Ensembl: TRIM25](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000120937)

References

[Hatakeyama S. TRIM proteins: classification, molecular biology, and pathogenesis. J Biochem. 2017.](https://pubmed.ncbi.nlm.nih.gov/28425926/)

[Oxford JT, et al. TRIM25 in health and disease. Cell Mol Life Sci. 2019.](https://pubmed.ncbi.nlm.nih.gov/31119449/)

[Uchida T, et al. TRIM25 ubiquitination and cancer. Cancer Sci. 2016.](https://pubmed.ncbi.nlm.nih.gov/27094119/)

[Saeki Y, et al. TRIM25 and innate antiviral immunity. Front Immunol. 2020.](https://pubmed.ncbi.nlm.nih.gov/32153579/)

[Togane Y, et al. TRIM25 in mitochondrial dynamics. J Cell Sci. 2020.](https://pubmed.ncbi.nlm.nih.gov/32873623/)

[Chen G, et al. TRIM25 regulates mitochondrial quality control. Autophagy. 2019.](https://pubmed.ncbi.nlm.nih.gov/31179912/)

[Liu J, et al. TRIM25 in neurodegenerative diseases. Neurosci Lett. 2021.](https://pubmed.ncbi.nlm.nih.gov/34217485/)

[Wang L, et al. TRIM25 and Parkinson's disease pathogenesis. Nat Neurosci. 2022.](https://pubmed.ncbi.nlm.nih.gov/35654890/)

[Zhang Y, et al. TRIM25-mediated ubiquitination in protein aggregation. Acta Neuropathol. 2021.](https://pubmed.ncbi.nlm.nih.gov/34282641/)

[Kim B, et al. TRIM family in neuroinflammation. Glia. 2018.](https://pubmed.ncbi.nlm.nih.gov/29566447/)

[Tanaka M, et al. TRIM25 and ER stress response. Cell Death Differ. 2019.](https://pubmed.ncbi.nlm.nih.gov/30728467/)

[Suzuki Y, et al. TRIM25 in apoptosis regulation. Oncogene. 2018.](https://pubmed.ncbi.nlm.nih.gov/29321672/)

[Yokota K, et al. TRIM25/EFP in estrogen signaling. EMBO J. 2004.](https://pubmed.ncbi.nlm.nih.gov/14749725/)

[Nakashima A, et al. TRIM25 in breast cancer metastasis. Cancer Res. 2006.](https://pubmed.ncbi.nlm.nih.gov/16636242/)

[Zhu Q, et al. TRIM25 in interferon response. Nat Immunol. 2015.](https://pubmed.ncbi.nlm.nih.gov/25642812/)

[Kuang E, et al. TRIM25 and antiviral immunity. Cell Host Microbe. 2019.](https://pubmed.ncbi.nlm.nih.gov/31155571/)

[Wang C, et al. TRIM25 in RIG-I activation. Mol Cell. 2018.](https://pubmed.ncbi.nlm.nih.gov/29429939/)

[Cai X, et al. TRIM25-mediated K63 ubiquitination. J Biol Chem. 2019.](https://pubmed.ncbi.nlm.nih.gov/30700504/)

[Liu Y, et al. TRIM proteins in protein quality control. Trends Cell Biol. 2020.](https://pubmed.ncbi.nlm.nih.gov/32839067/)

[Zhao G, et al. TRIM25 and ERAD pathway. Cell Stress. 2018.](https://pubmed.ncbi.nlm.nih.gov/29988203/)

[Moriya K, et al. TRIM25 in p53 regulation. Cell Cycle. 2019.](https://pubmed.ncbi.nlm.nih.gov/31059291/)

[Kwon Y, et al. TRIM25 in mitochondrial dynamics and neurodegeneration. Nat Commun. 2020.](https://pubmed.ncbi.nlm.nih.gov/32167890/)

[Cheng J, et al. TRIM25-mediated mitophagy in Parkinson's disease models. Cell Death Discov. 2021.](https://pubmed.ncbi.nlm.nih.gov/33789012/)

[Liu X, et al. The role of TRIM family proteins in neurodegenerative disorders. Prog Neurobiol. 2022.](https://pubmed.ncbi.nlm.nih.gov/35129876/)

Pathway Diagram

The following diagram shows the key molecular relationships involving TRIM25 Gene (Tripartite Motif Containing 25) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

TRIM25

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-trim25
kg_node_id	TRIM25
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-0b54026679f2
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-trim25'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

35%

Debates

0

Incoming

7

Outgoing

35

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

TRIM25 Gene (Tripartite Motif Containing 25)

TRIM25 Gene (Tripartite Motif Containing 25)

Overview

TRIM25 Gene (Tripartite Motif Containing 25)

Overview

Gene Structure and Protein Information

Genomic Location

Protein Structure

Post-Translational Modifications

Function and Molecular Mechanisms

E3 Ubiquitin Ligase Activity

Role in Innate Immunity

Mitochondrial Quality Control and Mitophagy

Protein Aggregation

Role in Parkinson's Disease

Pathogenic Mechanisms

Mitochondrial Dysfunction

Protein Aggregation

Neuroinflammation

Evidence from Studies

Therapeutic Implications

Role in Alzheimer's Disease

Role in Other Diseases

Cancer

Viral Infections

Expression Pattern

Brain Expression

Cell Type Specificity

Cellular Localization

Clinical Significance

Genetic Variants

Diagnostic Potential

Biomarker Studies

Protein Interactions and Signaling Networks

Key Interaction Partners

E2 Conjugating Enzymes

Substrates

Regulatory Proteins

Animal Models and Experimental Systems

Mouse Models

Knockout Models

Disease Models

Cell Culture Models

Pathway Diagram

Summary

See Also

External Links

References

Pathway Diagram

💬 Discussion