Figure 11. A Hypothetical Representation of DEP-mediated Suppression of M.tb-induced TLR Signaling and Effector Functions.

M.tb-derived ligands (LAM, 19 kDa protein, heat shock proteins 65 and 71, and M.tb DNA) bind to TLR2, 4 and 9 and recruit adaptor protein MyD88 (myloid differentiation primary protein 88) to the TLR receptor complex, which associates with IRAK1 and 4 (IL-1R-associated kinase). TRAF6 (tumor necrosis factor receptor-associated factor 6) is also recruited to the receptor complex following phosphorylation of IRAK1 by IRAK4. Association of TRAF6-IRAK complex with TAK1 (transforming growth factor-β-activated kinase) and TAB1 and 2 (TAK-binding protein 1 and 2) induces activation of TAK1 that phosphorylates IKK complex [inhibitor of nuclear factor-κB (IκB)-kinase complex] consisting of three subunits IKKα, β and γ. IKK complex phosphorylates IκB leading to its dissociation from NF-κB complex followed by translocation of NF-κB into the nucleus where NF-κB binds and activates target genes. In addition to MyD88, ligand binding to TLR4 recruits adaptor protein TRIF [Toll/IL-1R (TIR)-domain-containing adaptor protein inducing interferon-β], which associates with TBK1 (TANK-binding kinase 1) leading to the phosphorylation of IRF3 (interferon regulatory factor 3). Phosphorylated IRF3 translocates to the nucleus and induces production of Type I IFNs (48–50). DEP suppress M.tb-induced expression of target genes IL6, IL1A and PTGS2 via MyD88-dependent and Type I IFNs via MyD88-independent pathways. DEP-mediated downregulation of expression of TLR4, TLR7 and NF-κB target genes and Type I IFNs is shown by downward arrows.