TIR-domain-containing adapter-inducing interferon-β (TRIF) is an

adapter An adapter or adaptor is a device that converts attributes of one electrical device or system to those of an otherwise incompatible device or system. Some modify power or signal attributes, while others merely adapt the physical form of one c ...

in responding to activation of

toll-like receptors Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize s ...

(TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.

Toll-like receptors Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize s ...

(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 Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...

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.

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 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...

signaling pathway that leads to microbial evasion of immune response in the host after mutations occur within intermediates of the pathway. Three

TRAF TNF receptor associated factors (TRAFs) are a family of proteins primarily involved in the regulation of inflammation, antiviral responses and apoptosis. Currently, seven TRAF proteins have been characterized in mammals: TRAF1, TRAF2, TRAF3, TRAF4 ...

-binding motifs present in the amino terminal region of TRIF are necessary for association with

TRAF6 TRAF6 is a TRAF human protein. Function The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF recep ...

. Destruction of these motifs reduced the activation of NF-κB, 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 Toll-like receptor 3 (TLR3) also known as CD283 (cluster of differentiation 283) is a protein that in humans is encoded by the ''TLR3'' gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune ...

activation of NF-κB, 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-κB.

Areas of research

Investigations into the function of TRIF are of great significance to various fields of biomedical research. The

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

of infectious disease, septic shock,

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

growth, and

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

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.

References

External links

Toll-like receptor signaling pathway - Reference pathway (KO)
from the KEGG website. * {{TLR signaling pathway Immune system