toll-like receptor 8 signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by a ligand binding to the endolysosomal toll-like receptor 8. [GOC:add, PMID:16551253, PMID:17328678]

Toll-like receptor 8 (TLR8) is a transmembrane protein expressed primarily on immune cells like dendritic cells, macrophages, and B cells. It plays a crucial role in the innate immune response by recognizing and responding to specific pathogen-associated molecular patterns (PAMPs), particularly single-stranded RNA (ssRNA) molecules characteristic of viral and bacterial infections.

TLR8 signaling is initiated when ssRNA binds to the extracellular domain of TLR8, triggering a series of intracellular events. This binding leads to the dimerization of TLR8, bringing together two receptor molecules. The dimerization event activates the recruitment of adaptor proteins, primarily MyD88 (Myeloid differentiation primary response 88), via the Toll/IL-1 receptor (TIR) domain present in TLR8.

Once MyD88 is bound, it initiates a cascade of downstream signaling events. MyD88 interacts with IRAK4 (IL-1 receptor-associated kinase 4), leading to its phosphorylation and activation. Activated IRAK4 then interacts with and phosphorylates IRAK1 (IL-1 receptor-associated kinase 1). The IRAK1-IRAK4 complex, along with TRAF6 (TNF receptor-associated factor 6), subsequently associates with the E3 ubiquitin ligase complex, triggering the polyubiquitylation of TRAF6.

The polyubiquitylated TRAF6 molecule interacts with TAK1 (TGF-β-activated kinase 1), activating the MAP3K (mitogen-activated protein kinase kinase kinase) pathway. This activation leads to the phosphorylation and activation of downstream kinases, such as MKK3/6 and MKK4/7, which in turn activate the MAPKs (mitogen-activated protein kinases) p38, JNK, and ERK.

The activation of these MAPKs, along with the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, culminates in the expression of a range of pro-inflammatory cytokines and chemokines, including TNF-α (tumor necrosis factor alpha), IL-6 (interleukin 6), IL-12, and IFN-α (interferon alpha). These cytokines play a pivotal role in activating and recruiting other immune cells to the site of infection, thereby mounting an effective immune response against the invading pathogen.

In addition to activating NF-κB and MAPKs, TLR8 signaling can also induce the production of type I interferons (IFNs), particularly IFN-α, through the activation of the IRF (interferon regulatory factor) pathway. IFN-α plays a crucial role in controlling viral replication and promoting an antiviral state.

TLR8 signaling is tightly regulated to ensure appropriate immune responses and prevent excessive inflammation. Several negative regulators, including IRAK-M (interleukin-1 receptor-associated kinase M) and Tollip (Toll-interacting protein), are involved in downregulating TLR8 signaling.

In summary, TLR8 plays a crucial role in innate immunity by recognizing ssRNA and triggering the activation of downstream signaling pathways, leading to the production of pro-inflammatory cytokines and type I interferons, ultimately orchestrating an effective immune response against viral and bacterial infections.'
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Proteins (1)

Compounds (6)