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] 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.[6]
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.[7]
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.[8] Without this ubiquitination, there won’t be IFN production.
References
↑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. PMID7789997.
↑Haik KG (Jul 1985). "Visual difficulties from video display terminals". Southern Medical Journal. 78 (7): 887–8. doi:10.1097/00007611-198507000-00031.
↑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. PMID4042170.
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. PMID12943693.
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. PMID8889548.
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. PMID9245730.
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. PMID10781795.
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. PMID12075357.
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. PMID15130519.
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. PMID15592455.
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. PMID16144914.
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. PMID16271083.
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. PMID17069755.
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. PMID17418098.
