Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta [Tanimuro N et al 2008; Kagan JC et al 2008]. While TLR4 translocation to endosomes is governed by known regulators of general endocytic processes such as dynamins and clathrin, other proteins that specifically regulate LPS-stimulated TLR4 endocytosis have been also identified [Husebye et al 2006; Kagan JC et al 2008; Zanoni I et al 2011]. Thus, CD14 has been implicated both in transporting LPS to TLR4 and in delivering TLR4 to an endosomal compartment. TLR4 translocation activated by CD14 appears to be Syk-mediated, and requires its downstream effector phospholipase C gamma 2 (PLCgamma2), which in turn induces a drop in the concentration of PIP2 required for endosomal sealing [Zanoni I et al 2011]. It has also been shown that PLCgamma2 induces inositol 1,4,5-trisphosphate (IP(3)) production and subsequent calcium (Ca2+) release. Released intracellular Ca2+ was reported to mediate TLR4 trafficking and subsequent activation of IRF3. [Aki D et al 2008; Chiang CY et al 2012].
Aki, D, Minoda, Y, Yoshida, H, Watanabe, S, Yoshida, R, Takaesu, G, Chinen, T, Inaba, T, Hikida, M, Kurosaki, T, Saeki, K, Yoshimura, A
Husebye, H, Halaas, Ø, Stenmark, H, Tunheim, G, Sandanger, Ø, Bogen, B, Brech, A, Latz, E, Espevik, T
Chiang, CY, Veckman, V, Limmer, K, David, M
Kagan, JC, Su, T, Horng, T, Chow, A, Akira, S, Medzhitov, R
Zanoni, I, Ostuni, R, Marek, LR, Barresi, S, Barbalat, R, Barton, GM, Granucci, F, Kagan, JC
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