toll-like receptor TLR6:TLR2 signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by a ligand binding of a heterodimeric TLR6:TLR2 complex, followed by transmission of the signal by the activated receptor, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:nhn, GOC:signaling, PMID:17318230]

TLR6 and TLR2 are Toll-like receptors (TLRs) that recognize diacylated lipopeptides, a type of bacterial cell wall component. When TLR6 and TLR2 are activated by these lipopeptides, they initiate a signaling cascade that leads to the production of inflammatory cytokines and chemokines, ultimately triggering an immune response.

The process begins when a diacylated lipopeptide binds to the extracellular domain of TLR6 and TLR2, forming a heterodimer complex. This complex recruits the adaptor protein MyD88 (Myeloid differentiation primary response 88), which interacts with the intracellular Toll/IL-1 receptor (TIR) domain of TLR6/TLR2. The MyD88-TLR6/TLR2 complex then recruits another adaptor protein, IRAK4 (IL-1 receptor-associated kinase 4), which activates IRAK1 (IL-1 receptor-associated kinase 1).

Activated IRAK1 phosphorylates TRAF6 (TNF receptor-associated factor 6), a ubiquitin ligase that facilitates the assembly of a signaling complex containing TAK1 (TGF-beta-activated kinase 1) and its associated proteins, TAB1 and TAB2. Activated TAK1 phosphorylates IKK (IκB kinase), a key regulator of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells).

The phosphorylation of IKK leads to the degradation of IκBα (inhibitor of κB alpha), an inhibitory protein that prevents NF-κB from entering the nucleus. This allows NF-κB to translocate to the nucleus and activate the transcription of genes that encode inflammatory cytokines, such as TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), and IL-1β (interleukin-1 beta).

In addition to activating the NF-κB pathway, TLR6/TLR2 signaling can also activate the MAPK (mitogen-activated protein kinase) pathway. This pathway is activated by the phosphorylation of MEKK3 (MAPK/ERK kinase kinase 3) by TAK1, which subsequently activates the MAPK kinases, MKK3 and MKK6, leading to the phosphorylation of the MAPKs, p38 and JNK (c-Jun N-terminal kinase). Activated p38 and JNK then phosphorylate and activate transcription factors, such as ATF2 (activating transcription factor 2), which contribute to the expression of inflammatory genes.

Overall, the TLR6/TLR2 signaling pathway is a critical component of the innate immune system that enables the recognition and response to bacterial infections. This pathway is essential for the recruitment of immune cells to the site of infection, the production of inflammatory cytokines that promote the clearance of bacteria, and the activation of adaptive immune responses.
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Compounds (2)