Reactome | Endocytosis of TLR4:LY96:LPS:CD14

Endocytosis of TLR4:LY96:LPS:CD14

Stable Identifier

R-HSA-2201293

Type

Reaction [transition]

Species

Homo sapiens

Compartment

endosome membrane, plasma membrane

ReviewStatus

5/5

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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