TRIM25

Summary

TRIM25 (tripartite motif containing 25, HGNC:12932) is a protein-coding gene on chromosome 17q22, encoding E3 ubiquitin/ISG15 ligase TRIM25 (Q14258). Functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase.

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein is an RNA binding protein, functions as a ubiquitin E3 ligase and is involved in multiple cellular processes, including regulation of antiviral innate immunity.

Source: NCBI Gene 7706 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 99 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005082

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12932
Approved symbol	TRIM25
Name	tripartite motif containing 25
Location	17q22
Locus type	gene with protein product
Status	Approved
Aliases	EFP, RNF147
Ensembl gene	ENSG00000121060
Ensembl biotype	protein_coding
OMIM	600453
Entrez	7706

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 4 retained_intron, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 protein_coding

ENST00000316881, ENST00000537230, ENST00000570473, ENST00000570749, ENST00000572021, ENST00000572550, ENST00000573108, ENST00000574234, ENST00000574997, ENST00000648772, ENST00000682509, ENST00000682766

RefSeq mRNA: 1 — MANE Select: NM_005082 NM_005082

CCDS: CCDS11591

Canonical transcript exons

ENST00000316881 — 9 exons

Exon	Start	End
ENSE00001132203	56913392	56914049
ENSE00001217289	56887909	56892229
ENSE00003486381	56901419	56901578
ENSE00003487450	56908468	56908563
ENSE00003543644	56895926	56895952
ENSE00003567292	56899115	56899180
ENSE00003641678	56904255	56904488
ENSE00003658529	56895521	56895604
ENSE00003661427	56895343	56895441

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 98.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 52.5476 / max 925.0471, expressed in 1821 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167120	45.6309	1821
167119	5.1921	1243
167122	0.8027	114
167117	0.3836	79
167118	0.2268	77
167115	0.2088	93
167123	0.0860	49
167121	0.0167	5

Top tissues by expression

254 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.66	gold quality
blood	UBERON:0000178	96.62	gold quality
epithelial cell of pancreas	CL:0000083	96.60	gold quality
lower lobe of lung	UBERON:0008949	96.08	gold quality
jejunal mucosa	UBERON:0000399	95.00	gold quality
monocyte	CL:0000576	94.97	gold quality
vermiform appendix	UBERON:0001154	94.84	gold quality
thymus	UBERON:0002370	94.80	gold quality
leukocyte	CL:0000738	94.74	gold quality
skin of hip	UBERON:0001554	94.40	gold quality
spleen	UBERON:0002106	94.32	gold quality
bone marrow cell	CL:0002092	94.27	gold quality
caecum	UBERON:0001153	94.10	gold quality
gingival epithelium	UBERON:0001949	94.09	gold quality
gingiva	UBERON:0001828	93.90	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.73	gold quality
colonic mucosa	UBERON:0000317	93.63	gold quality
esophagus squamous epithelium	UBERON:0006920	93.54	gold quality
upper lobe of lung	UBERON:0008948	93.42	gold quality
mammary duct	UBERON:0001765	93.38	gold quality
upper lobe of left lung	UBERON:0008952	93.24	gold quality
pancreatic ductal cell	CL:0002079	93.22	gold quality
oviduct epithelium	UBERON:0004804	93.18	gold quality
rectum	UBERON:0001052	93.17	gold quality
epithelium of mammary gland	UBERON:0003244	93.16	gold quality
superficial temporal artery	UBERON:0001614	93.00	gold quality
duodenum	UBERON:0002114	93.00	gold quality
right uterine tube	UBERON:0001302	92.98	gold quality
granulocyte	CL:0000094	92.97	gold quality
kidney epithelium	UBERON:0004819	92.89	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.78

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
JUN	Activation
RIGI	Unknown

Upstream regulators (CollecTRI, top): ESR1, SP1, STAT1, USF1

miRNA regulators (miRDB)

76 targeting TRIM25, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-4708-3P	99.51	67.99	870

Literature-anchored findings (GeneRIF, showing 40)

• Efp controls breast cancer growth through ubiquitin-dependent proteolysis of 14-3-3sigma. (PMID:12943693)
• Results indicate that estrogen-responsive finger protein is widely expressed and may play important roles in various human tissues, possibly through estrogen receptors. (PMID:15130519)
• Over expression of Estrogen-responsive finger protein is associated with tumor progression of breast carcinoma (PMID:16144914)
• 14-3-3 sigma expression inversely correlated with estrogen receptor alpha, progesterone receptor and estrogen-responsive finger protein, and positively correlated with myometrial invasion and lymph node metastasis in endometrial adenocarcinoma (PMID:16271083)
• Efp is an IFN-responsive gene that potentially mediates IFN actions, involved in ISGylation and ubiquitination of proteins including Efp itself. (PMID:17069755)
• Our results indicate that EFP functions as a cofactor for ERalpha-mediated transcription. (PMID:17418098)
• role of the intact tandem CARD for TRIM25-mediated RIG-I activation; TRIM25 binds the RIG-I first CARD and subsequently ubiquitinates its second CARD (PMID:18948594)
• estradiol and tamoxifen may regulate the growth of endometrial carcinoma cells by stimulating VEGF production through Efp. (PMID:19148513)
• Viral nonstructural protein 1 inhibits activation of RIG-I by binding to TRIM25. (PMID:19454344)
• NS1 inhibits TRIM25-mediated RIG-I ubiquitination, thereby suppressing RIG-I signal transduction. (PMID:19454348)
• The regulation of Efp and bFGF expression during endometrial carcinogenesis suggests their potential utility as a prognostic biomarker. (PMID:20127022)
• Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains. (PMID:21266548)
• RING-IBR-RING E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding (PMID:21292167)
• Studies indicate that the splice variant of RIG-I encodes a protein that lacks the first CARD of RIG-I, and the variant RIG-I protein is not ubiquitinated by TRIM25. (PMID:21890623)
• EFP mediates estrogen-induced ATBF1 protein degradation in breast cancer cells. (PMID:22452784)
• 14-3-3epsilon is essential for the stable interaction of RIG-I with TRIM25, which facilitates RIG-I ubiquitination and initiation of innate immunity against hepatitis C virus and other pathogenic RNA viruses. (PMID:22607805)
• Study reports that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. (PMID:22626058)
• In controls, RNF125 is the highest expressed gene, whereas in HIV infection progressors, RIG-I is either the highest expressed gene or is expressed similarly to RNF125 and TRIM25. (PMID:24131985)
• Data indicate ubiquitin-specific protease 15 (USP15) as a critical regulator of the tripartite motif protein 25 (TRIM25)- and RNA sensor retinoic acid-inducible gene-I (RIG-I)-mediated antiviral immune response (PMID:24399297)
• Our data uncovers a previously unknown functional link between gp78 and TRIM25 and provides mechanistic insight into gp78-mediated protein ubiquitylation. (PMID:24810856)
• Trim25 binds to the conserved terminal loop (CTL) of pre-let-7 and activates TuT4, allowing for more efficient Lin28a-mediated uridylation. (PMID:25457611)
• Data show that TRIM25 enhances p53 and Mdm2 abundance by preventing their proteasomal degradation. At the same time, TRIM25 inhibits p53’s transcriptional activity and dampens the response to DNA damage. (PMID:25728675)
• expression of TRIM25 might be critical for lung cancer cell migration, proliferation as well as doxorubicin resistance. (PMID:26113559)
• The PR-2B DENV-2 produced increased levels of subgenomic flavivirus RNA (sfRNA) relative to genomic RNA during replication. PR-2B sfRNA showed sequence dependent binding to and prevention of tripartite motif 25 (TRIM25) deubiquitylation, which is critical for sustained and amplified retinoic acid-inducible gene 1 (RIG-I)-induced type I interferon expression. (PMID:26138103)
• TRIM25 plays an additional role in RIG-I/MDA5 signaling other than RIG-I ubiquitination via activation of NF-kappaB. (PMID:26299329)
• we provide a detailed characterization of the TRIM ligases TRIM25 and TRIM32 and show how their oligomeric state is linked to catalytic activity (PMID:27154206)
• TRIM25 actively participates in higher-order assembly of the RIG-I signalosome. (PMID:27425606)
• Studies showed that 70% of breast cancer patients were positive for Trim25 expression. (PMID:27528750)
• this study shows thatTRIM25 targets ERG for degradation in prostate cancer (PMID:27626314)
• Disturbed p53-MDM2 feedback loop contributing to the pathogenesis of thoracic aortic dissection may be linked to TRIM25 overexpression. (PMID:27903487)
• the data uncover TRIM25 as a bona fide zinc-finger antiviral protein cofactor that leads to increased zinc-finger antiviral protein modification enhancing its translational inhibition activity. (PMID:28060952)
• The severe acute respiratory syndrome coronavirus N protein was found to bind to the SPRY domain of the tripartite motif protein 25 (TRIM25) E3 ubiquitin ligase, thereby interfering with the association between TRIM25 and retinoic acid-inducible gene I (RIG-I) and inhibiting TRIM25-mediated RIG-I ubiquitination and activation. (PMID:28148787)
• these results demonstrate that type I IFN-induced TRIM25 is an important factor in inhibiting Hepatitis B virus replication (PMID:28194021)
• TRIM25 is required for Zinc finger antiviral protein optimal binding to target mRNA. (PMID:28202764)
• TRIM25 is a key determinant of breast cancer metastasis. (PMID:28813674)
• TRIM25 inhibits hepatocellular carcinoma progression by targeting MTA1. (PMID:28861931)
• Our results indicate that TRIM25 is associated with cisplatin resistance and 14-3-3sigma-MDM2-p53 signaling pathway is involved in this process, suggesting targeting TRIM25 may be a potential strategy for the reversal of cisplatin resistance. (PMID:28867193)
• The RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain, which we postulate to be a novel RNA-binding domain. (PMID:29117863)
• HPV E6 oncoprotein antagonizes the activation of the cytoplasmic innate immune sensor RIG-I by targeting its upstream regulatory enzymes TRIM25 and USP15. We further show that the RIG-I signaling cascade is important for an antiviral innate immune response to HPV16 infection (PMID:29263274)
• V interaction with TRIM25 and RIG-I prevents TRIM25-mediated ubiquitination of RIG-I and disrupts downstream RIG-I signaling to the mitochondrial antiviral signaling protein. (PMID:29321315)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Trim25	ENSMUSG00000000275
rattus_norvegicus	Trim25	ENSRNOG00000002341

Paralogs (80): MID2 (ENSG00000080561), TRIM9 (ENSG00000100505), MID1 (ENSG00000101871), MEFV (ENSG00000103313), TRIM35 (ENSG00000104228), TRIM14 (ENSG00000106785), TRIM37 (ENSG00000108395), TRIM2 (ENSG00000109654), TRIM3 (ENSG00000110171), TRIM38 (ENSG00000112343), TRIM62 (ENSG00000116525), TRIM67 (ENSG00000119283), TRIM32 (ENSG00000119401), BSPRY (ENSG00000119411), TRIM6 (ENSG00000121236), TRIM24 (ENSG00000122779), TRIM51 (ENSG00000124900), TRIM28 (ENSG00000130726), TRIM21 (ENSG00000132109), TRIM5 (ENSG00000132256), TRIM22 (ENSG00000132274), TRIM47 (ENSG00000132481), TRIM45 (ENSG00000134253), TRIM29 (ENSG00000137699), TRIM54 (ENSG00000138100), PML (ENSG00000140464), TRIM65 (ENSG00000141569), TRIM43B (ENSG00000144010), TRIM43 (ENSG00000144015), TRIM7 (ENSG00000146054), TRIM41 (ENSG00000146063), TRIM50 (ENSG00000146755), TRIM4 (ENSG00000146833), TRIM55 (ENSG00000147573), TRIM48 (ENSG00000150244), TRIM36 (ENSG00000152503), TRIM11 (ENSG00000154370), TRIM74 (ENSG00000155428), TRIM42 (ENSG00000155890), TRIM63 (ENSG00000158022)

Protein

Protein identifiers

E3 ubiquitin/ISG15 ligase TRIM25 — Q14258 (reviewed: Q14258)

Alternative names: Estrogen-responsive finger protein, RING finger protein 147, RING-type E3 ubiquitin transferase, RING-type E3 ubiquitin transferase TRIM25, Tripartite motif-containing protein 25, Ubiquitin/ISG15-conjugating enzyme TRIM25, Zinc finger protein 147

All UniProt accessions (3): A0A3B3IUA7, Q14258, I3L2W4

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a ubiquitin E3 ligase and as an ISG15 E3 ligase. Involved in innate immune defense against viruses by mediating ubiquitination of RIGI and IFIH1. Mediates ‘Lys-63’-linked polyubiquitination of the RIGI N-terminal CARD-like region and may play a role in signal transduction that leads to the production of interferons in response to viral infection. Mediates ‘Lys-63’-linked polyubiquitination of IFIH1. Promotes ISGylation of 14-3-3 sigma (SFN), an adapter protein implicated in the regulation of a large spectrum signaling pathway. Mediates estrogen action in various target organs. Mediates the ubiquitination and subsequent proteasomal degradation of ZFHX3. Plays a role in promoting the restart of stalled replication forks via interaction with the KHDC3L-OOEP scaffold and subsequent ubiquitination of BLM, resulting in the recruitment and retainment of BLM at DNA replication forks. Plays an essential role in the antiviral activity of ZAP/ZC3HAV1; an antiviral protein which inhibits the replication of certain viruses. Mechanistically, mediates ‘Lys-63’-linked polyubiquitination of ZAP/ZC3HAV1 that is required for its optimal binding to target mRNA. Also mediates the ubiquitination of various substrates implicated in stress granule formation, nonsense-mediated mRNA decay, nucleoside synthesis and mRNA translation and stability.

Subunit / interactions. Forms homodimers. Interacts (via SPRY domain) with RIGI (via CARD domain). Interacts with ZFHX3. Interacts with NLRP12; this interaction reduces the E3 ubiquitin ligase TRIM25-mediated ‘Lys-63’-linked RIGI activation. Interacts with the KHDC3L/FILIA-OOEP/FLOPED scaffold complex and BLM at DNA replication forks. Interacts with RTN3; this interaction prevents RIGI ubiquitination. Interacts with YWHAE. (Microbial infection) Interacts (via coiled coil) with influenza A virus NS1 protein; this interaction specifically inhibits TRIM25 multimerization and TRIM25-mediated RIGI CARD ubiquitination, thereby suppressing RIGI signal transduction. (Microbial infection) Interacts (via SPRY domain) with human respiratory syncytial virus (HRSV) non-structural protein 1; this interaction suppresses RIGI ubiquitination and results in decreased interaction between RIGI and MAVS. (Microbial infection) Interacts with JC virus small t antigen; this interaction suppresses RIGI ubiquitination thereby suppressing RIGI signal transduction. (Microbial infection) Interacts with paramyxoviruses (Sendai virus, Nipah virus, Measles virus and Parainfluenza virus 5) protein V; this interaction inhibits TRIM25-mediated ubiquitination of RIG-I and prevents downstream RIG-I signaling thereby inhibiting the IFN responses. (Microbial infection) Interacts with Severe fever with thrombocytopenia virus (SFTSV) NSs; this interaction this interaction sequesters TRIM25 in NSs-induced cytoplasmic inclusion bodies thereby inhibiting the IFN responses. (Microbial infection) Interacts with Epstein-Barr virus protein BPLF1 and YWHAZ; leading to inhibition of the type-I IFN response. (Microbial infection) Interacts with human metapneumovirus protein M2-2; this interaction suppresses RIGI ubiquitination thereby suppressing RIGI signal transduction.

Subcellular location. Cytoplasm. Stress granule. Nucleus.

Tissue specificity. Expressed in breast tumors (at protein level). Ubiquitous.

Post-translational modifications. Auto-ISGylated. (Microbial infection) Autoubiquitinated; promoted by Epstein-Barr virus protein BPLF1.

Activity regulation. RING domain dimerization is required for catalysis, TRIM25-mediated RIG-I ubiquitination, interferon induction, and antiviral activity.

Domain organisation. The RING-type zinc finger is important for ISG15 E3 ligase activity and autoISGylation. AutoISGylation negatively regulates ISG15 E3 ligase activity. The C-terminal B30.2/SPRY domain interacts with the first N-terminal CARD domain of RIGI.

Induction. By interferons.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_005073* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	Domain
IPR006574	PRY	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR027370	Znf-RING_euk	Domain
IPR042753	TRIM25_SPRY_PRY	Domain
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR051051	E3_ubiq-ligase_TRIM/RNF	Family
IPR058030	TRIM8/14/16/25/29/45/65_CC	Domain

Pfam: PF00622, PF13445, PF13765, PF25600

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (63 total): strand 17, helix 10, mutagenesis site 9, binding site 8, modified residue 5, turn 5, sequence variant 2, region of interest 2, chain 1, domain 1, cross-link 1, zinc finger region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9I0T	X-RAY DIFFRACTION	1.8
6FLM	X-RAY DIFFRACTION	2.01
5FER	X-RAY DIFFRACTION	2.34
5EYA	X-RAY DIFFRACTION	2.4
4LTB	X-RAY DIFFRACTION	2.59
9IUN	X-RAY DIFFRACTION	2.7
4CFG	X-RAY DIFFRACTION	2.8
5NT1	X-RAY DIFFRACTION	2.82
6FLN	X-RAY DIFFRACTION	3.6
5NT2	X-RAY DIFFRACTION	4.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14258-F1	84.78	0.68

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 33; 36; 50; 53; 13; 16; 28; 30

Post-translational modifications (6): 91, 100, 273, 278, 567, 117

Mutagenesis-validated functional residues (9):

Position	Phenotype
21	no effect on isgylation.
50	almost complete loss of zap/zc3hav1 ubiquitination; when associated with s-53.
53	almost complete loss of zap/zc3hav1 ubiquitination; when associated with s-50.
54	complete loss of viral inhibition independently of the host interferon response.
65	almost complete loss of ubiquitination activity.
65	no effect on isgylation.
71	almost complete loss of ubiquitination activity.
112	no effect on isgylation.
117	no isgylation.

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-877300	Interferon gamma signaling
R-HSA-918233	TRAF3-dependent IRF activation pathway
R-HSA-933541	TRAF6 mediated IRF7 activation
R-HSA-933542	TRAF6 mediated NF-kB activation
R-HSA-933543	NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-9833109	Evasion by RSV of host interferon responses
R-HSA-9833110	RSV-host interactions
R-HSA-9833482	PKR-mediated signaling
R-HSA-9909505	Modulation of host responses by IFN-stimulated genes
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses

MSigDB gene sets: 395 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (24): cytoplasmic pattern recognition receptor signaling pathway (GO:0002753), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), response to oxidative stress (GO:0006979), viral release from host cell (GO:0019076), regulation of protein localization (GO:0032880), response to vitamin D (GO:0033280), ERAD pathway (GO:0036503), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), response to estrogen (GO:0043627), suppression of viral release by host (GO:0044790), innate immune response (GO:0045087), regulation of viral entry into host cell (GO:0046596), host-mediated suppression of symbiont invasion (GO:0046597), protein K48-linked ubiquitination (GO:0070936), antiviral innate immune response (GO:0140374), cellular response to leukemia inhibitory factor (GO:1990830), immune system process (GO:0002376), mRNA transcription (GO:0009299), protein ubiquitination (GO:0016567), cellular response to oxidative stress (GO:0034599), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of DNA-templated transcription (GO:0045893), defense response to virus (GO:0051607)

GO Molecular Function (11): transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ligase activity (GO:0016874), RIG-I binding (GO:0039552), cadherin binding (GO:0045296), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), nuclear body (GO:0016604), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
DDX58/IFIH1-mediated induction of interferon-alpha/beta	5
Antimicrobial mechanism of IFN-stimulated genes	2
Interferon Signaling	2
Innate Immune System	1
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
Deubiquitination	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
RSV-host interactions	1
Respiratory Syncytial Virus Infection Pathway	1
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
defense response to virus	2
innate immune response	2
catalytic activity	2
positive regulation of cytokine production	1
pattern recognition receptor signaling pathway	1
intracellular receptor signaling pathway	1
modification-dependent protein catabolic process	1
response to stress	1
viral process	1
viral life cycle	1
exit from host cell	1
intracellular protein localization	1
regulation of localization	1
response to vitamin	1
response to lipid	1
response to oxygen-containing compound	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
response to hormone	1
immune response	1
defense response to symbiont	1
symbiont entry into host cell	1
modulation by symbiont of entry into host	1
regulation of viral life cycle	1
host-mediated perturbation of symbiont process	1
protein polyubiquitination	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
biological_process	1
DNA-templated transcription	1
mRNA metabolic process	1
protein modification by small protein conjugation	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

2042 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIM25	RIGI	O95786	998
TRIM25	IFIH1	Q9BYX4	938
TRIM25	MAVS	Q7Z434	932
TRIM25	YWHAE	P29360	862
TRIM25	DHX58	Q96C10	833
TRIM25	RNF125	Q96EQ8	831
TRIM25	UBE2L6	O14933	811
TRIM25	ISG15	P05161	788
TRIM25	EIF5A	P10159	783
TRIM25	USP15	Q9Y4E8	763
TRIM25	TRAT1	Q6PIZ9	762
TRIM25	SFN	P31947	754
TRIM25	IFNB1	P01574	749
TRIM25	IRF7	Q92985	746
TRIM25	EIF2AK2	P19525	744

IntAct

167 interactions, top by confidence:

A	B	Type	Score
G3BP1	N	psi-mi:“MI:0915”(physical association)	0.980
G3BP2	N	psi-mi:“MI:0915”(physical association)	0.970
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
N	TRIM25	psi-mi:“MI:0915”(physical association)	0.860
TRIM25	N	psi-mi:“MI:0915”(physical association)	0.860
N	TRIM25	psi-mi:“MI:0403”(colocalization)	0.860
TRIM25	RIGI	psi-mi:“MI:0914”(association)	0.850
TRIM25	RIGI	psi-mi:“MI:0915”(physical association)	0.850
TRIM25	RIGI	psi-mi:“MI:0403”(colocalization)	0.850
RIGI	TRIM25	psi-mi:“MI:0915”(physical association)	0.850
RIGI	TRIM25	psi-mi:“MI:0914”(association)	0.850
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
RIGI	N	psi-mi:“MI:0914”(association)	0.790
NSS	RIGI	psi-mi:“MI:0914”(association)	0.590
NSS	TRIM25	psi-mi:“MI:0403”(colocalization)	0.590
NSS	RIGI	psi-mi:“MI:0915”(physical association)	0.590
TRIM25	NSS	psi-mi:“MI:0915”(physical association)	0.590
NS	TRIM25	psi-mi:“MI:0915”(physical association)	0.560
TRIM25	NS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (2968): DDX58 (Biochemical Activity), TRIM25 (Reconstituted Complex), TRIM25 (Reconstituted Complex), TRIM25 (Reconstituted Complex), TRIM25 (Affinity Capture-MS), TRIM25 (Affinity Capture-MS), DDX58 (Biochemical Activity), TRIM25 (Affinity Capture-MS), TRIM25 (Affinity Capture-MS), TRIM25 (Affinity Capture-MS), TRIM25 (Affinity Capture-MS), DDX58 (Reconstituted Complex), TRIM25 (Affinity Capture-Western), DDX58 (Affinity Capture-Western), TRIM25 (Affinity Capture-MS)

ESM2 similar proteins: A1L4K1, D4A7V9, E9QHE3, F1LW30, H0UZ81, O15344, O70583, O95361, P82457, P82458, P97573, Q14258, Q14596, Q28CB1, Q38HM4, Q3UMR0, Q3V3A7, Q58D15, Q5F479, Q5R760, Q5RC94, Q5REJ9, Q5REW9, Q5RF77, Q5XIH6, Q61510, Q6P549, Q6P6S3, Q6UXZ4, Q7T2L7, Q7TNH6, Q7Z494, Q80VK6, Q80WG7, Q8BZ52, Q8JZL1, Q8K1S2, Q8NFM7, Q91Z63, Q969Q1

Diamond homologs: A0JPQ4, A6QQX5, D3YY23, D3Z8N2, F6ZQ54, F8S122, O00478, O00481, O60858, O75677, P18892, P82885, P83234, Q13410, Q14258, Q17RB8, Q1XH17, Q1XH18, Q27J48, Q2XXL4, Q32L60, Q503I2, Q5EBN2, Q5M7V1, Q5R846, Q5R996, Q5TA31, Q5ZMD4, Q61510, Q62556, Q640S6, Q6PGR9, Q6QA27, Q6UX41, Q6UXG8, Q6ZMU5, Q7SZN2, Q7T308, Q7TST0, Q810I1

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	TRIM25	ubiquitination
TRIM25	“up-regulates activity”	DDX58	polyubiquitination
LUBAC	“down-regulates quantity by destabilization”	TRIM25	polyubiquitination
TRIM25	“down-regulates quantity by destabilization”	MAVS	polyubiquitination
TRIM25	“down-regulates quantity by destabilization”	ZFHX3	polyubiquitination
TRIM25	“down-regulates quantity by destabilization”	AMFR	polyubiquitination
TRIM25	“down-regulates quantity by destabilization”	GPI	ubiquitination
SRC	“up-regulates activity”	TRIM25	phosphorylation
MAP3K13	“up-regulates quantity by stabilization”	TRIM25	phosphorylation
TRIM25	“down-regulates activity”	FBXW7	ubiquitination
TRIM25	“up-regulates activity”	ZC3HAV1	ubiquitination
TRIM25	“up-regulates activity”	DDX58	ubiquitination
TRIM25	“down-regulates quantity”	ERG	ubiquitination
TRIM25	“down-regulates quantity by destabilization”	SFN	ubiquitination
TRIM25	“down-regulates quantity by destabilization”	KLF5	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TICAM1, RIP1-mediated IKK complex recruitment	6	37.2×	6e-06
IKK complex recruitment mediated by RIP1	6	30.7×	1e-05
Ovarian tumor domain proteases	7	20.1×	1e-05
Negative regulators of DDX58/IFIH1 signaling	5	16.8×	1e-03
Respiratory Syncytial Virus Infection Pathway	5	10.2×	7e-03
RSV-host interactions	6	9.7×	3e-03
SARS-CoV-2 activates/modulates innate and adaptive immune responses	8	7.4×	1e-03
Infectious disease	17	4.3×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of interferon-alpha production	5	26.1×	7e-04
positive regulation of type I interferon production	5	17.0×	2e-03
axonogenesis	7	9.1×	2e-03
RNA splicing	9	6.4×	2e-03
DNA damage response	11	4.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

99 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3219 predictions. Top by Δscore:

Variant	Effect	Δscore
17:56844145:GATGC:G	donor_gain	1.0000
17:56844146:A:G	donor_gain	1.0000
17:56844176:GTG:G	donor_gain	1.0000
17:56848849:GATCG:G	donor_gain	1.0000
17:56848851:TCGG:T	donor_loss	1.0000
17:56848852:CGG:C	donor_loss	1.0000
17:56848853:GGT:G	donor_loss	1.0000
17:56848854:G:C	donor_loss	1.0000
17:56848854:G:GG	donor_gain	1.0000
17:56848855:T:G	donor_loss	1.0000
17:56858592:AGGC:A	acceptor_gain	1.0000
17:56858593:GGCG:G	acceptor_gain	1.0000
17:56858665:GGTAA:G	donor_loss	1.0000
17:56858666:GTAAG:G	donor_loss	1.0000
17:56858667:T:TC	donor_loss	1.0000
17:56861789:A:AG	acceptor_gain	1.0000
17:56861790:G:GG	acceptor_gain	1.0000
17:56861790:GCTA:G	acceptor_gain	1.0000
17:56862132:A:AG	acceptor_gain	1.0000
17:56862134:TTTTA:T	acceptor_loss	1.0000
17:56862135:TTTA:T	acceptor_loss	1.0000
17:56862136:TTAGG:T	acceptor_loss	1.0000
17:56862137:TAGG:T	acceptor_loss	1.0000
17:56862139:GGC:G	acceptor_gain	1.0000
17:56862250:GG:G	donor_gain	1.0000
17:56862251:GG:G	donor_gain	1.0000
17:56862801:G:GT	donor_gain	1.0000
17:56891791:T:C	donor_gain	1.0000
17:56895338:CTCA:C	donor_loss	1.0000
17:56895339:TCAC:T	donor_loss	1.0000

AlphaMissense

4130 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:56891739:A:C	F618L	0.998
17:56891739:A:T	F618L	0.998
17:56891741:A:G	F618L	0.998
17:56891747:A:G	W616R	0.998
17:56891747:A:T	W616R	0.998
17:56891912:A:G	W561R	0.998
17:56891912:A:T	W561R	0.998
17:56891948:A:G	W549R	0.998
17:56891948:A:T	W549R	0.998
17:56891951:A:G	S548P	0.998
17:56891962:C:G	R544P	0.998
17:56891965:C:T	G543D	0.998
17:56892053:A:G	W514R	0.998
17:56892053:A:T	W514R	0.998
17:56892108:G:C	F495L	0.998
17:56892108:G:T	F495L	0.998
17:56892109:A:G	F495S	0.998
17:56892110:A:G	F495L	0.998
17:56913893:G:C	F32L	0.998
17:56913893:G:T	F32L	0.998
17:56913895:A:G	F32L	0.998
17:56891851:A:G	L581P	0.997
17:56891854:A:G	L580P	0.997
17:56891963:G:T	R544S	0.997
17:56891965:C:A	G543V	0.997
17:56891966:C:G	G543R	0.997
17:56891971:C:G	R541T	0.997
17:56892014:C:G	G527R	0.997
17:56892020:C:A	G525W	0.997
17:56892024:G:C	F523L	0.997

dbSNP variants (sampled 300 via entrez): RS1000007940 (17:56915558 C>G), RS1000032272 (17:56906631 C>A), RS1000109223 (17:56894047 T>C), RS1000120344 (17:56915737 G>A), RS1000250769 (17:56909608 C>G), RS1000251674 (17:56905355 C>T), RS1000342317 (17:56911806 C>T), RS1000366852 (17:56896844 C>T), RS1000444422 (17:56902882 A>C,G), RS1000721793 (17:56910067 G>T), RS1000878468 (17:56903127 G>A,T), RS1000951449 (17:56890510 G>A), RS1001207871 (17:56893927 A>C), RS1001322487 (17:56894182 T>C), RS1001332961 (17:56910313 T>C)

Disease associations

OMIM: gene MIM:600453 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000175_3	Height	1.000000e-07
GCST008153_52	Lean body mass	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004995	lean body mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725068 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.28	Kd	52.79	nM	CHEMBL5653589
7.28	ED50	52.79	nM	CHEMBL5653589
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149655: Binding affinity to human TRIM25 incubated for 45 mins by Kinobead based pull down assay	kd	0.0528	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178633: Inhibition of TRIM25 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

62 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases activity	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, affects localization, decreases expression	3
bisphenol A	decreases expression, decreases methylation	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects expression	2
Estradiol	decreases reaction, increases expression	2
Lipopolysaccharides	increases expression, affects response to substance	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Tretinoin	affects cotreatment, decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
lead acetate	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	increases expression, decreases reaction	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
avobenzone	decreases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652697	Binding	Binding affinity to human TRIM25 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D8D3	Ubigene A-549 TRIM25 KO	Cancer cell line	Male
CVCL_D8XR	Ubigene HCT 116 TRIM25 KO	Cancer cell line	Male
CVCL_D9UY	Ubigene HEK293 TRIM25 KO	Transformed cell line	Female
CVCL_E0S7	Ubigene HeLa TRIM25 KO	Cancer cell line	Female
CVCL_TT95	HAP1 TRIM25 (-) 1	Cancer cell line	Male
CVCL_TT96	HAP1 TRIM25 (-) 2	Cancer cell line	Male
CVCL_TT97	HAP1 TRIM25 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.