TIRAP/Mal-deficient mice showed normal responses to the TLR3, TLR5, TLR7, and TLR9 ligands, but were defective in TLR4 and TLR2 ligand-induced proinflammatory cytokine production (Horng et al. 2002,Yamamoto et al. 2002). In contrast, TLR4 ligand-induced activation of IRF-3 and expression of IFN-inducible genes were not impaired in TIRAP/Mal knockout macrophages or in mice lacking both MyD88 and TIRAP/Mal (Horng et al. 2002,Yamamoto et al. 2002). Thus, TIRAP/Mal is an essential adapter that is involved in the MyD88-dependent pathway via TLR4 and TLR2, but not in the MyD88-independent pathway. Mal contains a phosphatidylinositol 4,5-bisphosphate-binding domain required for retention in the plasma membrane. The intracellular TIR domains of TLR2 or 4 associate with Mal at the cytoplasmic side of the plasma membrane, which in turn facilitates the binding of MyD88 to the activated TLR, leading to NF-kB and MAPK activation [Nunez Miguel et al 2007].
Yamamoto, M, Sato, S, Hemmi, H, Sanjo, H, Uematsu, S, Kaisho, T, Hoshino, K, Takeuchi, O, Kobayashi, M, Fujita, T, Takeda, K, Akira, S
Núñez Miguel, R, Wong, J, Westoll, JF, Brooks, HJ, O'Neill, LA, Gay, NJ, Bryant, CE, Monie, TP
Horng, T, Barton, GM, Flavell, RA, Medzhitov, R
Verstak, B, Nagpal, K, Bottomley, SP, Golenbock, DT, Hertzog, PJ, Mansell, A
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