TLR4:MD2:LPS:CD14 TLR4:MD2:LPS:CD14 Endocytosis of TLR4:MD2:LPS:CD14 Authored: Shamovsky, V, 2012-04-19 Edited: Shamovsky, V, 2012-05-25 Pubmed16467847 Pubmed18233961 Pubmed18297073 Pubmed22078883 Pubmed22158869 Reactome Database ID Release 432201293 Reactome, http://www.reactome.org ReactomeREACT_121112 Reviewed: D'Eustachio, P, 2012-05-25 Reviewed: Granucci, Francesca, Zanoni, Ivan, 2012-11-13 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].