Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
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]
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]
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]
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.
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