TRIM25

Tripartite motif containing 25
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4CFG​
Identifiers
Symbols	TRIM25 ; EFP; RNF147; Z147; ZNF147
External IDs	OMIM: 600453 MGI: 102749 HomoloGene: 48325 GeneCards: TRIM25 Gene
EC number	6.3.2.19, 6.3.2.n3
Gene ontology Molecular function • transcription factor activity, sequence-specific DNA binding • protein binding • zinc ion binding • acid-amino acid ligase activity • poly(A) RNA binding • ubiquitin protein ligase activity involved in ERAD pathway Cellular component • nucleoplasm • cytoplasm • cytosol Biological process • DNA repair • protein monoubiquitination • viral process • cytokine-mediated signaling pathway • translesion synthesis • negative regulation of type I interferon production • ERAD pathway • protein ubiquitination involved in ubiquitin-dependent protein catabolic process • positive regulation of I-kappaB kinase/NF-kappaB signaling • innate immune response • regulation of viral entry into host cell • negative regulation of viral entry into host cell • positive regulation of sequence-specific DNA binding transcription factor activity • positive regulation of NF-kappaB transcription factor activity • defense response to virus • interferon-gamma-mediated signaling pathway • regulation of viral release from host cell • negative regulation of viral release from host cell Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7706	217069
Ensembl	ENSG00000121060	ENSMUSG00000000275
UniProt	Q14258	Q61510
RefSeq (mRNA)	NM_005082	NM_009546
RefSeq (protein)	NP_005073	NP_033572
Location (UCSC)	Chr 17: 56.89 – 56.91 Mb	Chr 11: 89 – 89.02 Mb
PubMed search

Tripartite motif-containing protein 25 is a protein that in humans is encoded by the TRIM25 gene.^[1][2]

Function

The protein encoded by this gene is a member of the tripartite motif (TRIM) family grouping more than 70 TRIMs. TRIM proteins primarily function as ubiquitin ligases that regulate the innate response to infection.^[3] TRIM25 localizes to the cytoplasm. The presence of potential DNA-binding and dimerization-transactivation domains suggests that this protein may act as a transcription factor, similar to several other members of the TRIM family. Expression of the gene is upregulated in response to estrogen, and it is thought to mediate estrogen actions in breast cancer as a primary response gene.^[2]

Domain Architecture

TRIM25 has an N-terminal RING domain, followed by a B-box type 1 domain, a B-box type 2 domain, a coiled-coil domain (CCD) and a C-terminal SPRY domain. The RING domain coordinates two zinc atoms and is essential for recruiting ubiquitin-conjugating enzymes. The function of the B-box domains is unknown. The CCD domain has been implicated in multimerization and other protein-protein interactions.^[4] The SPRY domain is required for substrate recruitment.^[5]

TRIM25 functions

TRIM25 plays a key role in the RIG-I signaling pathway. RIG-I is a cytosolic pattern recognition receptor that senses viral RNA. Following RNA recognition, the caspase recruitment domain (CARD) of RIG-I undergoes K(63)-linked ubiquitination by TRIM25. The RING and SPRY domains of TRIM25 mediate its interaction with RIG-I. IFN production then follows by an intracellular signaling pathway involving IRF3.^[6]

Viral escape

To avoid IFN production, the non structural protein (NS1) of influenza will interact with CCD domain of TRIM25 to block RIG-I ubiquitination. Some studies have shown that a deletion of the CCD domain of TRIM25 prevents the binding of NS1.^[7] Without this ubiquitination, there won’t be IFN production.

References

1. Inoue S, Orimo A, Matsuda Y, Inazawa J, Emi M, Nakamura Y, Hori T, Muramatsu M (Jan 1995). "Chromosome mapping of human (ZNF147) and mouse genes for estrogen-responsive finger protein (efp), a member of the RING finger family". Genomics 25 (2): 581–3. doi:10.1016/0888-7543(95)80064-S. PMID 7789997.
2. "Entrez Gene: TRIM25 tripartite motif-containing 25".
3. D'Cruz AA, Kershaw NJ, Chiang JJ, Wang MK, Nicola NA, Babon JJ, Gack MU, Nicholson SE (2013). "Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling". The Biochemical Journal 456 (2): 231–40. doi:10.1042/BJ20121425. PMC 4012390. PMID 24015671.
4. Haik KG (Jul 1985). "Visual difficulties from video display terminals". Southern Medical Journal 78 (7): 887–8. PMC 4012390.
5. Pilka L, Trávník P, Dvorák M, Tesarík J, Ventruba P, Krejcí K, Soska J (Aug 1985). "[Delivery after intrauterine embryo transfer obtained by fertilization and oocyte culture in vitro]". Ceskoslovenská Gynekologie 50 (7): 452–9. PMC 4042170.
6. Gack MU, Kirchhofer A, Shin YC, Inn KS, Liang C, Cui S, Myong S, Ha T, Hopfner KP, Jung JU (Oct 2008). "Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction". Proceedings of the National Academy of Sciences of the United States of America 105 (43): 16743–8. doi:10.1073/pnas.0804947105. PMID 18948594.
7. Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, Farzan M, Inoue S, Jung JU, García-Sastre A (May 2009). "Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I". Cell Host & Microbe 5 (5): 439–49. doi:10.1016/j.chom.2009.04.006. PMID 19454348.

Further reading

• Horie K, Urano T, Ikeda K, Inoue S (Jun 2003). "Estrogen-responsive RING finger protein controls breast cancer growth". The Journal of Steroid Biochemistry and Molecular Biology 85 (2-5): 101–4. doi:10.1016/S0960-0760(03)00209-7. PMID 12943693.
• Inoue S, Orimo A, Hosoi T, Kondo S, Toyoshima H, Kondo T, Ikegami A, Ouchi Y, Orimo H, Muramatsu M (Dec 1993). "Genomic binding-site cloning reveals an estrogen-responsive gene that encodes a RING finger protein". Proceedings of the National Academy of Sciences of the United States of America 90 (23): 11117–21. doi:10.1073/pnas.90.23.11117. PMC 47933. PMID 8248217.
• Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Ikeda K, Inoue S, Orimo A, Sano M, Watanabe T, Tsutsumi K, Muramatsu M (Jul 1997). "Multiple regulatory elements and binding proteins of the 5'-flanking region of the human estrogen-responsive finger protein (efp) gene". Biochemical and Biophysical Research Communications 236 (3): 765–71. doi:10.1006/bbrc.1997.7046. PMID 9245730.
• Ikeda K, Orimo A, Higashi Y, Muramatsu M, Inoue S (Apr 2000). "Efp as a primary estrogen-responsive gene in human breast cancer". FEBS Letters 472 (1): 9–13. doi:10.1016/S0014-5793(00)01421-6. PMID 10781795.
• Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A (May 2001). "The tripartite motif family identifies cell compartments". The EMBO Journal 20 (9): 2140–51. doi:10.1093/emboj/20.9.2140. PMC 125245. PMID 11331580.
• Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, Ouchi Y, Inoue S (Jun 2002). "Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth". Nature 417 (6891): 871–5. doi:10.1038/nature00826. PMID 12075357.
• Shimada N, Suzuki T, Inoue S, Kato K, Imatani A, Sekine H, Ohara S, Shimosegawa T, Sasano H (Apr 2004). "Systemic distribution of estrogen-responsive finger protein (Efp) in human tissues". Molecular and Cellular Endocrinology 218 (1-2): 147–53. doi:10.1016/j.mce.2003.12.008. PMID 15130519.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (Jan 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology 23 (1): 94–101. doi:10.1038/nbt1046. PMID 15592455.
• Suzuki T, Urano T, Tsukui T, Horie-Inoue K, Moriya T, Ishida T, Muramatsu M, Ouchi Y, Sasano H, Inoue S (Sep 2005). "Estrogen-responsive finger protein as a new potential biomarker for breast cancer". Clinical Cancer Research 11 (17): 6148–54. doi:10.1158/1078-0432.CCR-05-0040. PMID 16144914.
• Nakayama H, Sano T, Motegi A, Oyama T, Nakajima T (Nov 2005). "Increasing 14-3-3 sigma expression with declining estrogen receptor alpha and estrogen-responsive finger protein expression defines malignant progression of endometrial carcinoma". Pathology International 55 (11): 707–15. doi:10.1111/j.1440-1827.2005.01900.x. PMID 16271083.
• Nakasato N, Ikeda K, Urano T, Horie-Inoue K, Takeda S, Inoue S (Dec 2006). "A ubiquitin E3 ligase Efp is up-regulated by interferons and conjugated with ISG15". Biochemical and Biophysical Research Communications 351 (2): 540–6. doi:10.1016/j.bbrc.2006.10.061. PMID 17069755.
• Nakajima A, Maruyama S, Bohgaki M, Miyajima N, Tsukiyama T, Sakuragi N, Hatakeyama S (May 2007). "Ligand-dependent transcription of estrogen receptor alpha is mediated by the ubiquitin ligase EFP". Biochemical and Biophysical Research Communications 357 (1): 245–51. doi:10.1016/j.bbrc.2007.03.134. PMID 17418098.