TLR-TRIF Pathway
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TLR-TRIF Pathway
TLRs (Toll-like receptors) are key molecules of the innate immune system that recognize molecular patterns on microorganisms and rapidly alert the host to the presence of potentially dangerous organisms. When TLRs on the surface of an immune cell are engaged, two major events are triggered downstream. First, all TLRs trigger the secretion of intercellular messenger proteins called cytokines, which initiate and perpetuate inflammation. In most cases, the production of inflammatory cytokines in response to TLR stimulation depends on a common molecular pathway that is anchored by an adaptor protein MyD88 (Myeloid Differentiation Primary Response Gene 88). This protein contains a structural region called a TIR (Toll/Interleukin-1 Receptor) domain, which allows it to associate with the intracellular tail of a TLR and to connect the receptor to molecules like serine/threonine kinase IRAK (Interleukin-1 Receptor-Associated Kinase), TRAF6 (TNF Receptor-Associated Factor-6) and TAK1 (TGF-Beta-Activated Kinase-1), which propagate a signal further inside the cell. The IRAK family consists of two active kinases, IRAK1 and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. IRAK-M expression is restricted to monocytes/macrophages, whereas other IRAKs are ubiquitous. IRAK-M is induced upon TLR stimulation and negatively regulates TLR signaling. The pathway culminates in the nucleus with the activation of appropriate genes, such as cytokine genes (Ref.1). Second, the stimulation of the TLR3 and TLR4 receptors also triggers unique signals that activate IRF3 (Interferon Regulatory Factor-3), independent of MyD88, which lead to the secretion of Interferon-Beta. This protein subsequently causes the activation of a series of genes whose products help to eliminate the pathogen (Ref.2). TRIF (TIR domain-containing adapter inducing IFN-Beta), also called TICAM1 (TIR-containing adaptor molecule-1), is a recently identified protein involved in MyD88-independent signaling pathways triggered by TLRs. TRIF/TICAM1 is a key adapter in MyD88-independent pathway of TLR3 signaling but seems also to be involved in the signaling pathways of other TLRs such as TLR2, TLR4 and TLR7. TLR3 is crucial for viral immunity as it detects the presence of the double-stranded RNAs that occur in some viral genomes. TRIF/TICAM1, which is expressed ubiquitously, binds preferentially to TLR3 and requires dimerization. Distinct domains of TRIF/TICAM1 are involved in the activation of the IFN-Beta and NF-KappaB promoters: IFN-Beta promoter activation is mediated by the N-terminal portion of TRIF/TICAM1 whereas NF-KappaB (Nuclear Factor-KappaB) promoter activation requires both N-terminal and C-terminal portions of TRIF/TICAM1. The TIR domain of TRIF/TICAM1 shares little similarity with the TIR domains of MyD88 and TIRAP, however TRIF/TICAM1 contains the proline in the so-called BB loop that is essential for TIR-MyD88 mediated signaling. Another difference with MyD88 and TIRAP is the absence of a death domain in TRIF/TICAM1 (Ref.3). TRIF is also essential in transducing signals from bacterial LPS (Lipopolysaccharide), via TLR4, for Interferon-Beta production. MyD88, MAL (MyD88 Adaptor-Like protein) or TIRAP and TRIF can potentially interact with TLR4 and contribute to downstream signal transduction, that included phosphorylation of ERK1/2 (Extracellular signal-Regulated Kinase-1/2), p38and JNK (Jun N-terminal kinase) and activation of NF-KappaB (Nuclear Factor-KappaB) (Ref.4).

The TRIF protein, identified genetically as Lps2, associates with different "receptors" that detect a virus or a bacterium on the surfaces of human cells. TRIF is a signal transducer--it helps turn these positive detections into immune reactions. Significantly, TRIF is the topmost protein shared by the pathway that detects Gram-negative bacteria and the pathway that detects most viruses. In addition, TRIF could be a potential target for intervening in diseases in which the innate immune system plays a role, such as sepsis. Sepsis basically results from a runaway cascade of inflammation in response to a bacterial infection, and TRIF is involved very early in this cascade. If drugs might be designed that could modulate the function of TRIF, they might help to improve the prognosis for sepsis (Ref.5).