TRIM25

TRIM25
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4CFG, 4LTB, 5FER
Identifiers
Aliases	TRIM25 , EFP, RNF147, Z147, ZNF147, tripartite motif containing 25
External IDs	OMIM: 600453; MGI: 102749; HomoloGene: 48325; GeneCards: TRIM25; OMA:TRIM25 - orthologs
EC number	2.3.2.27
Gene location (Human) Chr. Chromosome 17 (human) [1] Band 17q22 Start 56,836,387 bp [1] End 56,914,080 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11|11 C Start 88,890,202 bp [2] End 88,911,119 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of ileum blood pancreatic epithelial cell lower lobe of lung jejunal mucosa monocyte appendix thymus skin of hip spleen Top expressed in Paneth cell medullary collecting duct renal corpuscle semi-lunar valve conjunctival fornix retinal pigment epithelium ciliary body endothelial cell of lymphatic vessel ureter epithelium of stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity DNA-binding transcription factor activity ubiquitin protein ligase activity metal ion binding ligase activity protein binding ubiquitin-protein transferase activity RNA binding cadherin binding zinc ion binding Cellular component nucleoplasm cytoplasm cytosol nuclear body intracellular anatomical structure Biological process ERAD pathway negative regulation of viral entry into host cell immune system process interferon-gamma-mediated signaling pathway positive regulation of DNA-binding transcription factor activity protein monoubiquitination defense response to virus positive regulation of NF-kappaB transcription factor activity protein ubiquitination positive regulation of I-kappaB kinase/NF-kappaB signaling translesion synthesis negative regulation of type I interferon production innate immune response viral process response to estrogen response to vitamin D protein deubiquitination ubiquitin-dependent ERAD pathway cellular response to leukemia inhibitory factor ubiquitin-dependent protein catabolic process regulation of viral entry into host cell Sources:Amigo / QuickGO
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: 56.84 – 56.91 Mb Chr 11: 88.89 – 88.91 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tripartite motif-containing protein 25 is a protein that in humans is encoded by the TRIM25 gene. ^{[5] [6]}

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. ^[7] 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. ^[6]

Structure

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. ^[8] The SPRY domain is required for substrate recruitment. ^[9] The NMR chemical shifts for backbone of the PRYSPRY domain of TRIM25 is assigned based on triple-resonance experiments using uniformly isotopic labeled protein and the secondary structure of the domain PRYSPRY domain of TRIM25 predicted based on the NMR assignments. ^[10]

Function

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. ^[11] Results obtained in human TRIM25 knock-out cells suggest that it may not play a key role in RIG-I activation. ^{[12] [13] [14]} These studies revealed that another E3 ubiquitin ligase RIPLET (RNF135), not TRIM25, is sufficient to ubiquitinate and activate the RIG-I.

TRIM25 has been shown to be an RNA-binding protein. ^{[15] [16] [17]} TRIM25 binds RNAs (either single- or double-stranded) through an RNA-binding domain (RBD) residing in its C-terminal PRY/SPRY region in conjunction with CCD. ^{[18] [19]} RNA-binding appears to be important for TRIM25 ubiquitin ligase activity. ^[18] Some data suggest that it can destabilise viral mRNA. ^{[14] [12]}

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. ^[20] Without this ubiquitination, there won’t be IFN production.

References

1. GRCh38: Ensembl release 89: ENSG00000121060 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000000275 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Inoue S, Orimo A, Matsuda Y, Inazawa J, Emi M, Nakamura Y, et al. (January 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): 581–583. doi:10.1016/0888-7543(95)80064-S. PMID   7789997.
6. "Entrez Gene: TRIM25 tripartite motif-containing 25".
7. D'Cruz AA, Kershaw NJ, Chiang JJ, Wang MK, Nicola NA, Babon JJ, et al. (December 2013). "Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling". The Biochemical Journal. 456 (2): 231–240. doi:10.1042/BJ20121425. PMC   4012390 . PMID   24015671.
8. Haik KG (July 1985). "Visual difficulties from video display terminals". Southern Medical Journal. 78 (7): 887–888. doi:10.1097/00007611-198507000-00031. PMID   4012390.
9. Li Y, Wu H, Wu W, Zhuo W, Liu W, Zhang Y, et al. (June 2014). "Structural insights into the TRIM family of ubiquitin E3 ligases". Cell Research. 24 (6): 762–765. doi:10.1038/cr.2014.46. PMC   4042170 . PMID   24722452.
10. Kong C, Penumutchu SR, Hung KW, Huang H, Lin T, Yu C (October 2015). "Backbone resonance assignments of the PRYSPRY domain of TRIM25". Biomolecular NMR Assignments. 9 (2): 313–315. doi:10.1007/s12104-015-9599-x. PMID   25702035. S2CID   11475584.
11. Gack MU, Kirchhofer A, Shin YC, Inn KS, Liang C, Cui S, et al. (October 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): 16743–16748. Bibcode:2008PNAS..10516743G. doi: 10.1073/pnas.0804947105 . PMC   2575490 . PMID   18948594.
12. Cadena C, Ahmad S, Xavier A, Willemsen J, Park S, Park JW, et al. (May 2019). "Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity". Cell. 177 (5): 1187–1200.e16. doi:10.1016/j.cell.2019.03.017. PMC   6525047 . PMID   31006531.
13. Hayman TJ, Hsu AC, Kolesnik TB, Dagley LF, Willemsen J, Tate MD, et al. (October 2019). "RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses". Immunology and Cell Biology. 97 (9): 840–852. doi:10.1111/imcb.12284. PMID   31335993.
14. Choudhury NR, Trus I, Heikel G, Wolczyk M, Szymanski J, Bolembach A, et al. (July 2022). "TRIM25 inhibits influenza A virus infection, destabilizes viral mRNA, but is redundant for activating the RIG-I pathway". Nucleic Acids Research. 50 (12): 7097–7114. doi:10.1093/nar/gkac512. PMC   9262604 . PMID   35736141.
15. Choudhury NR, Nowak JS, Zuo J, Rappsilber J, Spoel SH, Michlewski G (November 2014). "Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation". Cell Reports. 9 (4): 1265–1272. doi:10.1016/j.celrep.2014.10.017. PMC   4542301 . PMID   25457611.
16. Kwon SC, Yi H, Eichelbaum K, Föhr S, Fischer B, You KT, et al. (September 2013). "The RNA-binding protein repertoire of embryonic stem cells". Nature Structural & Molecular Biology. 20 (9): 1122–1130. doi:10.1038/nsmb.2638. PMID   23912277.
17. Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, et al. (June 2012). "Insights into RNA biology from an atlas of mammalian mRNA-binding proteins". Cell. 149 (6): 1393–1406. doi:10.1016/j.cell.2012.04.031. PMID   22658674.
18. Choudhury NR, Heikel G, Trubitsyna M, Kubik P, Nowak JS, Webb S, et al. (November 2017). "RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination". BMC Biology. 15 (1): 105. doi: 10.1186/s12915-017-0444-9 . PMC   5678581 . PMID   29117863.
19. Álvarez L, Haubrich K, Iselin L, Gillioz L, Ruscica V, Lapouge K, et al. (October 2024). "The molecular dissection of TRIM25's RNA-binding mechanism provides key insights into its antiviral activity". Nature Communications. 15 (1): 8485. Bibcode:2024NatCo..15.8485A. doi:10.1038/s41467-024-52918-x. PMC   11445558 . PMID   39353916.
20. Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, et al. (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): 439–449. doi:10.1016/j.chom.2009.04.006. PMC   2737813 . PMID   19454348.

Further reading

• Horie K, Urano T, Ikeda K, Inoue S (June 2003). "Estrogen-responsive RING finger protein controls breast cancer growth". The Journal of Steroid Biochemistry and Molecular Biology. 85 (2–5): 101–104. doi:10.1016/S0960-0760(03)00209-7. PMID   12943693. S2CID   22487508.
• Inoue S, Orimo A, Hosoi T, Kondo S, Toyoshima H, Kondo T, et al. (December 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): 11117–11121. Bibcode:1993PNAS...9011117I. doi: 10.1073/pnas.90.23.11117 . PMC   47933 . PMID   8248217.
• Bonaldo MF, Lennon G, Soares MB (September 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, et al. (July 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): 765–771. doi:10.1006/bbrc.1997.7046. PMID   9245730.
• Ikeda K, Orimo A, Higashi Y, Muramatsu M, Inoue S (April 2000). "Efp as a primary estrogen-responsive gene in human breast cancer". FEBS Letters. 472 (1): 9–13. Bibcode:2000FEBSL.472....9I. doi: 10.1016/S0014-5793(00)01421-6 . PMID   10781795. S2CID   10570937.
• Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, et al. (May 2001). "The tripartite motif family identifies cell compartments". The EMBO Journal. 20 (9): 2140–2151. doi:10.1093/emboj/20.9.2140. PMC   125245 . PMID   11331580.
• Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, et al. (June 2002). "Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth". Nature. 417 (6891): 871–875. Bibcode:2002Natur.417..871U. doi:10.1038/nature00826. PMID   12075357. S2CID   4348545.
• Shimada N, Suzuki T, Inoue S, Kato K, Imatani A, Sekine H, et al. (April 2004). "Systemic distribution of estrogen-responsive finger protein (Efp) in human tissues". Molecular and Cellular Endocrinology. 218 (1–2): 147–153. doi:10.1016/j.mce.2003.12.008. PMID   15130519. S2CID   44761828.
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, et al. (January 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID   15592455. S2CID   7200157.
• Suzuki T, Urano T, Tsukui T, Horie-Inoue K, Moriya T, Ishida T, et al. (September 2005). "Estrogen-responsive finger protein as a new potential biomarker for breast cancer". Clinical Cancer Research. 11 (17): 6148–6154. doi:10.1158/1078-0432.CCR-05-0040. PMID   16144914. S2CID   11698115.
• Nakayama H, Sano T, Motegi A, Oyama T, Nakajima T (November 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): 707–715. doi:10.1111/j.1440-1827.2005.01900.x. PMID   16271083. S2CID   7106422.
• Nakasato N, Ikeda K, Urano T, Horie-Inoue K, Takeda S, Inoue S (December 2006). "A ubiquitin E3 ligase Efp is up-regulated by interferons and conjugated with ISG15". Biochemical and Biophysical Research Communications. 351 (2): 540–546. doi:10.1016/j.bbrc.2006.10.061. PMID   17069755.
• Nakajima A, Maruyama S, Bohgaki M, Miyajima N, Tsukiyama T, Sakuragi N, et al. (May 2007). "Ligand-dependent transcription of estrogen receptor alpha is mediated by the ubiquitin ligase EFP". Biochemical and Biophysical Research Communications. 357 (1): 245–251. doi:10.1016/j.bbrc.2007.03.134. hdl: 2115/24261 . PMID   17418098.