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>
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<td class="label">Full Name</td>
<td>TRIM25 (Tripartite Motif Containing 25)</td>
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<td class="label">Type</td>
<td>Gene</td>
</tr>
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<td class="label">NCBI</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/?term=TRIM25" target="_blank">Search NCBI</a></td>
</tr>
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<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>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">55 edges</a></td>
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</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].
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 substrateTRIM25 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.
See Also
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Mitochondrial Quality Control](/mechanisms/mitochondrial-quality-control)
- [Mitophagy](/mechanisms/mitophagy)
- [Ubiquitin-Proteasome System](/mechanisms/ups)
- [Neuroinflammation](/mechanisms/neuroinflammation)
- [Alpha-Synuclein](/proteins/alpha-synuclein)
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)