A brief description of general TLR signaling pathway

<b>A general overview of TLR signaling pathways. </b>The full names of proteins shown in the figure are as follows. MyD88: Myeloid differentiation primary response protein 88; TIRAP: TIR-domain-containing adaptor protein; IRAK1: IL-1R-associated kinase 1; TRAF6: Tumor-necrosis-factor receptor-associated factor 6; IKK: Inhibitor of nuclear factor-κB (IκB)-kinase; IRF3: Interferon regulatory factor 3; TBK1: TRAF family member-associated NF-kappa-B activator (TANK) binding kinase; TRIF: TIR domain-containing adaptor–inducing interferon-β; TRAM: TRIF-related adaptor molecule. Two different but simultaneous pathways of signal transduction are known by which TLRs activate an adaptive immune response. One is through the adaptor MyD88, which is used by all TLRs except for TLR3. TLR3 operates through the TRIF pathway. TLR4 signals through both TRIF and MyD88 pathways. In the MyD88 pathway (also called the canonical pathway), conformational alteration of TLR homo/heterodimers allows binding of the TLR-TIR domain to the MyD88-TIR domains through homotypic TIR-TIR interaction. Subsequently, MyD88 recruits the kinase IRAK4 by death domain (DD)-DD interactions. IRAK4 binds and phosphorylates IRAK1, a natural substrate of IRAK4. Phosphorylated IRAK1 brings TRAF6 to the receptor complex. TRAF6 and IRAK1 dissociate from the receptor complex and form another complex with transforming growth factor β activated kinase 1 (TAK1), which coexists with the adaptor TAK1-binding protein 2 (TAB2) and activator TAB1 at the plasma membrane. IRAK1 phosphorylates both TAB1 and TAK1, and is degraded afterward, facilitating the translocation of TRAF6, TAK1, TAB1, and TAB2 to the cytoplasm where ubiquitin-conjugating enzyme 13 (UBC13) and ubiquitin-conjugating enzyme E2 variant 1 (UEV1A) ubiquitinate TRAF6, inducing activation of TAK1. Next, TAK1 phosphorylates mitogen-activated protein kinase (MAPK) and IKK complexes. The IKK complex, in turn, phosphorylates the IκB subunit of NF-κB, leading to its ubiquitination and subsequent degradation. This allows nuclear translocation of NF-κB to induce transcription of target genes. MyD88 works in concert with an upstream DD-lacking adaptor TIRAP, also called MyD88 adaptor-like (MAL), particularly during TLR1/2, 2/6, and TLR4 signaling. The TRIF pathway, also called the MyD88-independent or alternate signaling pathway, is specifically activated by TLR3 and TLR4. TRIF, along with a second, upstream adaptor, TRAM, stimulates IKK-ε and TBK1. IKK-ε, the counterpart of IKK in the canonical pathway, and TBK1 mediate activation and nuclear translocation of IRF3 to induce transcription of antiviral IFNs.<b></b>The figure was redrawn from the published paper (own: http://dx.doi.org/10.1080/13543776.2016.1185415). The figure is uploaded in Wikicommons https://commons.wikimedia.org/wiki/File:TLR_Signaling_pathway.tif