Trif

protein
Name=toll-like receptor adaptor molecule 1
caption=


width=
HGNCid=18348
Symbol=TICAM1
AltSymbols=TRIF
EntrezGene=148022
OMIM=607601
RefSeq=NM_014261
UniProt=Q8IUC6
PDB=
ECnumber=
Chromosome=19
Arm=p
Band=13.3
LocusSupplementaryData=

TIR-domain-containing adapter-inducing interferon-β (TRIF) is is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter. [Palsson-McDermott, Eva and Luke A J O’Neill (2004) Immunology. 113(2) 153-162]

Toll-like receptors (TLRs) recognize specific components of microbial invaders and activate an immune response to these pathogens. After these receptors recognize highly-conserved pathogenic patterns, a downstream signaling cascade is activated in order to stimulate the release of inflammatory cytokines and chemokines as well as to upregulate the expression of immune cells. All TLRs have a TIR domain that initiates the signaling cascade through TIR adapters. Adapters are platforms that organize downstream signaling cascades leading to a specific cellular response after exposure to a given pathogen. [cite journal |author=Guo B, Cheng G |title=Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK |journal=J. Biol. Chem. |volume=282 |issue=16 |pages=11817–26 |year=2007 |pmid=17327220 |doi=10.1074/jbc.M700017200]

Structure

TRIF is primarily active in the spleen and is often regulated when MyD88 is deficient in the liver, indicating organ-specific regulation of signaling pathways. Curiously, there is a lack of redundancy within the TLR4 signaling pathway that leads to microbial evasion of immune response in the host after mutations occur within intermediates of the pathway. [Palsson-McDermott, Eva and Luke A J O’Neill (2004) Immunology. 113(2) 153-162] Three TRAF-binding motifs present in the amino terminal region of TRIF are necessary for association with TRAF6. Destruction of these motifs reduced the activation of NF-κβ, a transcription factor that is also activated by the carboxy-terminal domain of TRIF in the upregulation of cytokines and co-stimulatory immune molecules. This domain recruits receptor-interacting protein (RIP1) and RIP3 through the RIP homotypic interaction motif. Cells deficient for RIP1 gene display attenuated TLR3 activation of NF-κβ, indicating the use of the RIP1 gene in downstream TRIF activation, in contrast to other TLRs that use IRAK protein for the activation of NF-κβ. [Kawai, Taro and Shizuo Akira. (2004). Arthritis Res. Ter. 7(1) 12-19]

Function

The TRIF cascade is a MyD88-independent signaling pathway associated with TLR3 and TLR4. A second adapter protein identified as "TRAM" (TRIF-related adaptor molecule [ [http://www.jbc.org/cgi/reprint/280/7/5491.pdf Transforming Growth Factor- Differentially Inhibits MyD88 ...] ] ) acts as an essential bridge between TRIF and TLR4, acting upstream of the TRIF protein. These TIR domain-containing adapters are differentially recruited to TLRs upon stimulation by pathogenic patterns. [Boraschi, Diana and Aldo Tagliabue. “The interleukin-1 receptor family”. (2006). Vitamins and Hormones. 74: 229-54] The TRIF cascade results in the activation of IRF-3, which then activates interferons α and β, which are essentially for an inflammatory immune response. This pathway also stimulates NF-κβ, which upregulates costimulatory molecules CD40, CD80, and CD86 that in turn activate T-cell production and immune response. Overproduction of these molecules, however, can also lead to organ failure and death. Therefore, regulation of these pathways is crucial. A member of the TIR-domain superfamily, TIR8/SIGIRR is unable to initiate signaling but is able to negatively modulate the TIR-mediated responses. [Boraschi, Diana and Aldo Tagliabue. “The interleukin-1 receptor family”. (2006). Vitamins and Hormones. 74: 229-54] A variety of other regulatory molecules, as well as cooperation between MyD88-dependent and –independent pathways act to ensure an appropriate amount of immune response.

Areas of research

Investigations into the function of TRIF are of great significance to various fields of biomedical research. The pathogenesis of infectious disease, septic shock, tumor growth, and rheumatoid arthritis all have close ties with TLR signaling pathways, specifically to that of TRIF. Better understanding of the TRIF pathway will be therapeutically useful in the development of vaccines and treatments that can control associated inflammation and antiviral responses. Experiments involving wild-type and TRIF-deficient mice are critical for understanding the coordinated responses of TLR pathways. It is necessary to study the coordinated effects of these pathways in order to understand the complex responses initiated by TRIF. [cite journal |author=Ouyang X, Negishi H, Takeda R, Fujita Y, Taniguchi T, Honda K |title=Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation |journal=Biochem. Biophys. Res. Commun. |volume=354 |issue=4 |pages=1045–51 |year=2007 |pmid=17275788 |doi=10.1016/j.bbrc.2007.01.090]

References

External links

* [http://www.genome.ad.jp/dbget-bin/www_bget?path:ko04620 Toll-like receptor signaling pathway - Reference pathway (KO)] from the KEGG website.
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