NDLI: Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1–IKKϵ

Content Provider	Journal of Biological Chemistry (JBC)
Author	Tsukamoto, Hiroki Takeuchi, Shino Kubota, Kanae Kobayashi, Yohei Kozakai, Sao Ukai, Ippo Shichiku, Ayumi Okubo, Misaki Numasaki, Muneo Kanemitsu, Yoshitomi Matsumoto, Yotaro Nochi, Tomonori Watanabe, Kouichi Aso, Hisashi Tomioka, Yoshihisa
Abstract	Toll-like receptor 4 (TLR4) is an indispensable immune receptor for lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall. Following LPS stimulation, TLR4 transmits the signal from the cell surface and becomes internalized in an endosome. However, the spatial regulation of TLR4 signaling is not fully understood. Here, we investigated the mechanisms of LPS-induced TLR4 internalization and clarified the roles of the extracellular LPS-binding molecules, LPS-binding protein (LBP), and glycerophosphatidylinositol-anchored protein (CD14). LPS stimulation of CD14-expressing cells induced TLR4 internalization in the presence of serum, and an inhibitory anti-LBP mAb blocked its internalization. Addition of LBP to serum-free cultures restored LPS-induced TLR4 internalization to comparable levels of serum. The secretory form of the CD14 (sCD14) induced internalization but required a much higher concentration than LBP. An inhibitory anti-sCD14 mAb was ineffective for serum-mediated internalization. LBP lacking the domain for LPS transfer to CD14 and a CD14 mutant with reduced LPS binding both attenuated TLR4 internalization. Accordingly, LBP is an essential serum molecule for TLR4 internalization, and its LPS transfer to membrane-anchored CD14 (mCD14) is a prerequisite. LBP induced the LPS-stimulated phosphorylation of TBK1, IKKϵ, and IRF3, leading to IFN-β expression. However, LPS-stimulated late activation of NF-κB or necroptosis were not affected. Collectively, our results indicate that LBP controls LPS-induced TLR4 internalization, which induces TLR adaptor molecule 1 (TRIF)-dependent activation of the TBK1–IKKϵ–IRF3–IFN-β pathway. In summary, we showed that LBP-mediated LPS transfer to mCD14 is required for serum-dependent TLR4 internalization and activation of the TRIF pathway.
Related Links	http://www.jbc.org/content/293/26/10186.abstract
Ending Page	10201
Starting Page	10186
Page Count	16
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	26
Volume Number	293
DOI	10.1074/jbc.M117.796631
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2018-06-29
Access Restriction	Open
Subject Keyword	Cell-surface receptor Endotoxin Innate immunity Lipopolysaccharide (LPS) Pathogen-associated molecular pattern (PAMP) Pattern recognition receptor (PRR) TIR-domain-containing adapter-inducing interferon-B (TRIF) Toll-like receptor 4 (TLR4) CD14 LPS-binding protein (LBP) Cell Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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