negative regulation of toll-like receptor 3 signaling pathway

Definition

Target type: biologicalprocess

Any process that stops, prevents, or reduces the frequency, rate, or extent of toll-like receptor 3 signaling pathway. [GOC:add, PMID:16551253, PMID:17328678]

Negative regulation of Toll-like receptor 3 (TLR3) signaling pathway is a crucial cellular process that dampens the immune response triggered by viral double-stranded RNA (dsRNA). TLR3, a pattern recognition receptor located on endosomal membranes, recognizes dsRNA and initiates a signaling cascade that ultimately activates transcription factors such as interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB). These transcription factors drive the expression of type I interferons (IFNs) and pro-inflammatory cytokines, which play critical roles in antiviral defense. However, unrestrained TLR3 signaling can lead to excessive inflammation and tissue damage. Therefore, multiple negative regulatory mechanisms have evolved to ensure appropriate control of TLR3 signaling.

One key regulatory mechanism involves the recruitment of inhibitory adaptor proteins, such as Toll-interacting protein (TOLLIP) and Trif-related adaptor molecule (TRAM), to the TLR3 signaling complex. These proteins can compete with TRIF, the adaptor molecule essential for TLR3-mediated activation of downstream signaling pathways, thereby preventing TRIF recruitment and signal propagation.

Another regulatory strategy involves the activation of negative feedback loops. For example, the production of type I IFNs can induce the expression of suppressor of cytokine signaling (SOCS) proteins, which act as inhibitors of downstream signaling pathways. SOCS proteins can directly interact with signaling molecules, such as Janus kinases (JAKs) and STATs, to suppress their activity, thereby attenuating the TLR3 signaling response.

Additionally, the ubiquitination and degradation of signaling molecules, such as TRIF and IRF3, can also contribute to the downregulation of TLR3 signaling. This process is mediated by E3 ubiquitin ligases, which specifically target key signaling components for ubiquitination, leading to their proteasomal degradation.

Furthermore, several post-translational modifications, such as phosphorylation and acetylation, can influence the activity of TLR3 signaling components. For example, phosphorylation of TRIF at specific residues can negatively regulate its ability to activate downstream signaling pathways.

Finally, the expression of microRNAs (miRNAs), small non-coding RNAs that regulate gene expression, can also contribute to the negative regulation of TLR3 signaling. Certain miRNAs have been shown to target TLR3 signaling molecules, reducing their expression levels and dampening the signaling response.

Overall, negative regulation of TLR3 signaling pathway is a complex process that involves multiple mechanisms, including inhibitory adaptor proteins, negative feedback loops, ubiquitination and degradation, post-translational modifications, and miRNA-mediated regulation. These intricate regulatory mechanisms ensure that the immune response to viral dsRNA is tightly controlled, preventing excessive inflammation and maintaining cellular homeostasis.'
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Proteins (1)

Compounds (4)