Endocytosis of TLR4:LY96:LPS:CD14

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Reaction [transition]
Homo sapiens
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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].
Literature References
PubMed ID Title Journal Year
16467847 Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity

Sandanger, Ø, Husebye, H, Latz, E, Bogen, B, Brech, A, Tunheim, G, Halaas, Ø, Espevik, T, Stenmark, H

EMBO J 2006
18233961 Peptidoglycan and lipopolysaccharide activate PLCgamma2, leading to enhanced cytokine production in macrophages and dendritic cells

Yoshida, H, Chinen, T, Hikida, M, Minoda, Y, Saeki, K, Inaba, T, Kurosaki, T, Yoshida, R, Watanabe, S, Aki, D, Yoshimura, A, Takaesu, G

Genes Cells 2008
22158869 Phospholipase C?-2 and intracellular calcium are required for lipopolysaccharide-induced Toll-like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation

Chiang, CY, David, M, Limmer, K, Veckman, V

J Biol Chem 2012
18297073 TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta

Horng, T, Kagan, JC, Su, T, Akira, S, Chow, A, Medzhitov, R

Nat Immunol 2008
22078883 CD14 controls the LPS-induced endocytosis of Toll-like receptor 4

Barton, GM, Granucci, F, Kagan, JC, Barresi, S, Barbalat, R, Ostuni, R, Zanoni, I, Marek, LR

Cell 2011
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