TRIM25

{{Short description|Protein-coding gene in the species Homo sapiens}}

Tripartite motif-containing protein 25 is a protein that in humans is encoded by the TRIM25 gene.{{cite journal | vauthors = Inoue S, Orimo A, Matsuda Y, Inazawa J, Emi M, Nakamura Y, Hori T, Muramatsu M | title = Chromosome mapping of human (ZNF147) and mouse genes for estrogen-responsive finger protein (efp), a member of the RING finger family | journal = Genomics | volume = 25 | issue = 2 | pages = 581–583 | date = January 1995 | pmid = 7789997 | doi = 10.1016/0888-7543(95)80064-S }}{{cite web | title = Entrez Gene: TRIM25 tripartite motif-containing 25| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7706}}

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.{{cite journal | vauthors = D'Cruz AA, Kershaw NJ, Chiang JJ, Wang MK, Nicola NA, Babon JJ, Gack MU, Nicholson SE | title = Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling | journal = The Biochemical Journal | volume = 456 | issue = 2 | pages = 231–240 | date = December 2013 | pmid = 24015671 | pmc = 4012390 | doi = 10.1042/BJ20121425 }} 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.

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.{{cite journal | vauthors = Haik KG | title = Visual difficulties from video display terminals | journal = Southern Medical Journal | volume = 78 | issue = 7 | pages = 887–888 | date = July 1985 | pmid = 4012390 | doi = 10.1097/00007611-198507000-00031 }} The SPRY domain is required for substrate recruitment.{{cite journal | vauthors = Li Y, Wu H, Wu W, Zhuo W, Liu W, Zhang Y, Cheng M, Chen YG, Gao N, Yu H, Wang L, Li W, Yang M | title = Structural insights into the TRIM family of ubiquitin E3 ligases | journal = Cell Research | volume = 24 | issue = 6 | pages = 762–765 | date = June 2014 | pmid = 24722452 | pmc = 4042170 | doi = 10.1038/cr.2014.46 }} 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.{{cite journal | vauthors = Kong C, Penumutchu SR, Hung KW, Huang H, Lin T, Yu C | title = Backbone resonance assignments of the PRYSPRY domain of TRIM25 | journal = Biomolecular NMR Assignments | volume = 9 | issue = 2 | pages = 313–315 | date = October 2015 | pmid = 25702035 | doi = 10.1007/s12104-015-9599-x | s2cid = 11475584 }}

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.{{cite journal | vauthors = Gack MU, Kirchhofer A, Shin YC, Inn KS, Liang C, Cui S, Myong S, Ha T, Hopfner KP, Jung JU | title = Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 43 | pages = 16743–16748 | date = October 2008 | pmid = 18948594 | pmc = 2575490 | doi = 10.1073/pnas.0804947105 | doi-access = free | bibcode = 2008PNAS..10516743G }} Results obtained in human TRIM25 knock-out cells suggest that it may not play a key role in RIG-I activation.{{cite journal | vauthors = Cadena C, Ahmad S, Xavier A, Willemsen J, Park S, Park JW, Oh SW, Fujita T, Hou F, Binder M, Hur S | title = Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity | journal = Cell | volume = 177 | issue = 5 | pages = 1187–1200.e16 | date = May 2019 | pmid = 31006531 | pmc = 6525047 | doi = 10.1016/j.cell.2019.03.017 }}{{cite journal | vauthors = Hayman TJ, Hsu AC, Kolesnik TB, Dagley LF, Willemsen J, Tate MD, Baker PJ, Kershaw NJ, Kedzierski L, Webb AI, Wark PA, Kedzierska K, Masters SL, Belz GT, Binder M, Hansbro PM, Nicola NA, Nicholson SE | title = RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses | journal = Immunology and Cell Biology | volume = 97 | issue = 9 | pages = 840–852 | date = October 2019 | pmid = 31335993 | doi = 10.1111/imcb.12284 }}{{cite journal | vauthors = Choudhury NR, Trus I, Heikel G, Wolczyk M, Szymanski J, Bolembach A, Dos Santos Pinto RM, Smith N, Trubitsyna M, Gaunt E, Digard P, Michlewski G | title = TRIM25 inhibits influenza A virus infection, destabilizes viral mRNA, but is redundant for activating the RIG-I pathway | journal = Nucleic Acids Research | volume = 50 | issue = 12 | pages = 7097–7114 | date = July 2022 | pmid = 35736141 | pmc = 9262604 | doi = 10.1093/nar/gkac512 }} 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. {{cite journal | vauthors = Choudhury NR, Nowak JS, Zuo J, Rappsilber J, Spoel SH, Michlewski G | title = Trim25 Is an RNA-Specific Activator of Lin28a/TuT4-Mediated Uridylation | journal = Cell Reports | volume = 9 | issue = 4 | pages = 1265–1272 | date = November 2014 | pmid = 25457611 | pmc = 4542301 | doi = 10.1016/j.celrep.2014.10.017 }}{{cite journal | vauthors = Kwon SC, Yi H, Eichelbaum K, Föhr S, Fischer B, You KT, Castello A, Krijgsveld J, Hentze MW, Kim VN | title = The RNA-binding protein repertoire of embryonic stem cells | journal = Nature Structural & Molecular Biology | volume = 20 | issue = 9 | pages = 1122–1130 | date = September 2013 | pmid = 23912277 | doi = 10.1038/nsmb.2638 }}{{cite journal | vauthors = Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, Davey NE, Humphreys DT, Preiss T, Steinmetz LM, Krijgsveld J, Hentze MW | title = Insights into RNA biology from an atlas of mammalian mRNA-binding proteins | journal = Cell | volume = 149 | issue = 6 | pages = 1393–1406 | date = June 2012 | pmid = 22658674 | doi = 10.1016/j.cell.2012.04.031 }} 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. {{cite journal | vauthors = Choudhury NR, Heikel G, Trubitsyna M, Kubik P, Nowak JS, Webb S, Granneman S, Spanos C, Rappsilber J, Castello A, Michlewski G | title = RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination | journal = BMC Biology | volume = 15 | issue = 1 | pages = 105 | date = November 2017 | pmid = 29117863 | doi = 10.1186/s12915-017-0444-9 | doi-access = free | pmc = 5678581 }}{{cite journal | vauthors = Álvarez L, Haubrich K, Iselin L, Gillioz L, Ruscica V, Lapouge K, Augsten S, Huppertz I, Choudhury NR, Simon B, Masiewicz P, Lethier M, Cusack S, Rittinger K, Gabel F, Leitner A, Michlewski G, Hentze MW, Allain FH, Castello A, Hennig J | title = The molecular dissection of TRIM25's RNA-binding mechanism provides key insights into its antiviral activity | journal = Nature Communications | volume = 15 | issue = 1 | pages = 8485 | date = October 2024 | pmid = 39353916 | pmc = 11445558 | doi = 10.1038/s41467-024-52918-x | bibcode = 2024NatCo..15.8485A }} RNA-binding appears to be important for TRIM25 ubiquitin ligase activity. Some data suggest that it can destabilise viral mRNA.{{cite journal | vauthors = Cadena C, Ahmad S, Xavier A, Willemsen J, Park S, Park JW, Oh SW, Fujita T, Hou F, Binder M, Hur S | title = Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity | journal = Cell | volume = 177 | issue = 5 | pages = 1187–1200.e16 | date = May 2019 | pmid = 31006531 | pmc = 6525047 | doi = 10.1016/j.cell.2019.03.017 }}

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.{{cite journal | vauthors = Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, Farzan M, Inoue S, Jung JU, García-Sastre A | title = Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I | journal = Cell Host & Microbe | volume = 5 | issue = 5 | pages = 439–449 | date = May 2009 | pmid = 19454348 | pmc = 2737813 | doi = 10.1016/j.chom.2009.04.006 }} Without this ubiquitination, there won’t be IFN production.

TRIM25

Structure

Function

Viral escape

References

Further reading