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].
Westoll, JF, Brooks, HJ, Wong, J, O'Neill, LA, Núñez Miguel, R, Gay, NJ, Monie, TP, Bryant, CE
Takeuchi, O, Hoshino, K, Sanjo, H, Fujita, T, Sato, S, Yamamoto, M, Takeda, K, Akira, S, Kaisho, T, Uematsu, S, Kobayashi, M, Hemmi, H
Barton, GM, Horng, T, Medzhitov, R, Flavell, RA
Bottomley, SP, Nagpal, K, Verstak, B, Mansell, A, Hertzog, PJ, Golenbock, DT
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