toll-like receptor 3 signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by a ligand binding to the endolysosomal toll-like receptor 3. [GOC:add, PMID:16551253, PMID:17328678]

Toll-like receptor 3 (TLR3) is a transmembrane protein that recognizes double-stranded RNA (dsRNA), a hallmark of viral infections. When TLR3 encounters dsRNA, it triggers a signaling cascade that ultimately leads to the activation of transcription factors, such as interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB), which induce the expression of antiviral genes. This intricate signaling process involves several key components and steps:

1. **Ligand Recognition:** TLR3 is localized within intracellular compartments, including endosomes and lysosomes. When dsRNA enters these compartments, it binds to the extracellular domain of TLR3.

2. **Adaptor Protein Recruitment:** Upon dsRNA binding, TLR3 recruits the adaptor protein TRIF (Toll/IL-1 receptor domain-containing adaptor inducing interferon-β) through its Toll/IL-1 receptor (TIR) domain.

3. **TRIF-Mediated Signaling:** TRIF acts as a scaffold, assembling downstream signaling components. It interacts with TRAF6 (TNF receptor-associated factor 6) and RIP1 (receptor-interacting protein kinase 1), leading to the activation of two distinct pathways:

* **TRAF6-Mediated Pathway:** TRAF6 activates the TAK1 (TGF-β-activated kinase 1) complex, which phosphorylates IKK (IκB kinase) and activates NF-κB. NF-κB then translocates to the nucleus and induces the expression of pro-inflammatory cytokines, such as TNF-α and IL-6.

* **RIP1-Mediated Pathway:** RIP1 interacts with the kinase TBK1 (TANK-binding kinase 1) and IKKε (IKK epsilon), which subsequently phosphorylate and activate IRF3. IRF3 translocates to the nucleus and stimulates the transcription of type I interferons (IFN-α and IFN-β), which have potent antiviral activity.

4. **Antiviral Gene Expression:** The production of IFN-α and IFN-β triggers a cascade of antiviral responses, including:

* **Inhibition of Viral Replication:** IFN-α and IFN-β induce the expression of interferon-stimulated genes (ISGs), which directly interfere with viral replication by various mechanisms, such as blocking viral entry, inhibiting protein synthesis, and degrading viral RNA.

* **Immune Cell Activation:** IFN-α and IFN-β activate immune cells, such as natural killer (NK) cells and macrophages, to eliminate virus-infected cells. They also enhance the antigen presentation process, facilitating adaptive immune responses.

5. **Negative Feedback Regulation:** To prevent excessive immune activation and potential tissue damage, TLR3 signaling is tightly regulated by negative feedback mechanisms. These mechanisms involve the degradation of signaling components, such as TRIF, and the activation of inhibitory proteins, such as A20 (TNFAIP3), which dampens NF-κB activity.

Overall, TLR3 signaling plays a critical role in host defense against viral infections. By recognizing dsRNA and triggering the production of interferons and pro-inflammatory cytokines, TLR3 initiates a robust antiviral response that helps control viral spread and protect the organism.'
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Proteins (6)

Compounds (133)