DOI QR코드

DOI QR Code

Dynamic lipopolysaccharide transfer cascade to TLR4/MD2 complex via LBP and CD14

  • Kim, Soo Jin (Graduate School of Medical Science & Engineering, KAIST) ;
  • Kim, Ho Min (Graduate School of Medical Science & Engineering, KAIST)
  • Received : 2017.01.21
  • Published : 2017.02.28

Abstract

Toll-like receptor 4 (TLR4) together with MD2, one of the key pattern recognition receptors for a pathogen-associated molecular pattern, activates innate immunity by recognizing lipopolysaccharide (LPS) of Gram-negative bacteria. Although LBP and CD14 catalyze LPS transfer to the TLR4/MD2 complex, the detail mechanisms underlying this dynamic LPS transfer remain elusive. Using negative-stain electron microscopy, we visualized the dynamic intermediate complexes during LPS transfer-LBP/LPS micelles and ternary CD14/LBP/LPS micelle complexes. We also reconstituted the entire cascade of LPS transfer to TLR4/MD2 in a total internal reflection fluorescence (TIRF) microscope for a single molecule fluorescence analysis. These analyses reveal longitudinal LBP binding to the surface of LPS micelles and multi-round binding/unbinding of CD14 to single LBP/LPS micelles via key charged residues on LBP and CD14. Finally, we reveal that a single LPS molecule bound to CD14 is transferred to TLR4/MD2 in a TLR4-dependent manner. These discoveries, which clarify the molecular mechanism of dynamic LPS transfer to TLR4/MD2 via LBP and CD14, provide novel insights into the initiation of innate immune responses.

Acknowledgement

Supported by : Ministry of Health and Welfare

Cited by

  1. Activating transcription factor 3 protects mice against pseudomonas aeruginosa-induced acute lung injury by interacting with lipopolysaccharide binding protein vol.90, 2017, https://doi.org/10.1016/j.molimm.2017.06.037
  2. Peripheral Blood Monocyte Tolerance Alleviates Intraperitoneal Lipopolysaccharides-Induced Neuroinflammation in Rats Via Upregulating the CD200R Expression 2017, https://doi.org/10.1007/s11064-017-2334-5
  3. Protective effects of sinomenine against LPS-induced inflammation in piglets vol.110, 2017, https://doi.org/10.1016/j.micpath.2017.07.044
  4. Bacterial lipids: powerful modifiers of the innate immune response vol.6, 2017, https://doi.org/10.12688/f1000research.11388.1
  5. TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis vol.5, pp.4, 2017, https://doi.org/10.3390/vaccines5040034
  6. Bioactive polysaccharides from natural resources including Chinese medicinal herbs on tissue repair vol.13, pp.1, 2018, https://doi.org/10.1186/s13020-018-0166-0
  7. Pathogen- and Danger-Associated Molecular Patterns and the Cytokine Response in Sepsis vol.19, pp.2, 2018, https://doi.org/10.1089/sur.2017.264
  8. Exploring the biological functional mechanism of the HMGB1/TLR4/MD-2 complex by surface plasmon resonance vol.24, pp.1, 2018, https://doi.org/10.1186/s10020-018-0023-8
  9. Released Tryptophanyl-tRNA Synthetase Stimulates Innate Immune Responses against Viral Infection vol.93, pp.2, 2018, https://doi.org/10.1128/JVI.01291-18
  10. Fasciola hepatica GST downregulates NF-κB pathway effectors and inflammatory cytokines while promoting survival in a mouse septic shock model vol.9, pp.1, 2019, https://doi.org/10.1038/s41598-018-37652-x
  11. Mice vol.2019, pp.2314-7156, 2019, https://doi.org/10.1155/2019/3737890
  12. Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain vol.9, pp.1, 2019, https://doi.org/10.1038/s41598-018-37409-6
  13. Alveolar-Capillary Membrane-Related Pulmonary Cells as a Target in Endotoxin-Induced Acute Lung Injury vol.20, pp.4, 2019, https://doi.org/10.3390/ijms20040831