Tripartite motif-containing protein 25 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''TRIM25''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
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
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquiti ...
that regulate the innate response to infection.
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.
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 enzyme
Ubiquitin-conjugating enzymes, also known as E2 enzymes and more rarely as ''ubiquitin-carrier enzymes'', perform the second step in the ubiquitination reaction that targets a protein for degradation via the proteasome. The ubiquitination process ...
s. The function of the B-box domains is unknown. The CCD domain has been implicated in multimerization and other protein-protein interactions. The SPRY domain is required for substrate recruitment. 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.
TRIM25 functions
TRIM25 plays a key role in the
RIG-I
RIG-I (retinoic acid-inducible gene I) is a cytosolic pattern recognition receptor (PRR) responsible for the type-1 interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infect ...
signaling pathway. RIG-I is a cytosolic
pattern recognition receptor
Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...
that senses viral RNA. Following RNA recognition, the
caspase recruitment domain
Caspase recruitment domains, or caspase activation and recruitment domains (CARDs), are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate th ...
(CARD) of RIG-I undergoes K(63)-linked
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
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
Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor.
Function
IRF3 is a member of the interferon regulatory transcription factor (IRF) family. IRF3 was originally discovered as a homolog of IRF1 and IRF2. ...
.
Viral escape
To avoid IFN production, the non structural protein (
NS1) of
influenza
Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
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.
Without this ubiquitination, there won’t be IFN production.
References
Further reading
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