Lipopolysaccharide Is in Close Proximity to Each of the Proteins in Its Membrane Receptor Complex

By Jean da Silva Correia, K. Soldau, U. Christen, P. Tobias, R. Ulevitch. Journal of Biological Chemistry, 2001

720 citations recorded by the source corpus.

The structural features of some proteins of the innate immune system involved in mediating responses to microbial pathogens are highly conserved throughout evolution. Examples include members of the Drosophila Toll (dToll) and the mammalian Toll-like receptor (TLR) protein families. Activation ofDrosophila Toll is believed to occur via an endogenous peptide rather than through direct binding of microbial products to the Toll protein. In mammals there is a growing consensus that lipopolysaccharide (LPS) initiates its biological activities through a heteromeric receptor complex containing CD14, TLR4, and at least one other protein, MD-2. LPS binds directly to CD14 but whether LPS then binds to TLR4 and/or MD-2 is not known. We have used transient transfection to express human TLRs, MD-2, or CD14 alone or in different combinations in HEK 293 cells. Interactions between LPS and these proteins were studied using a chemically modified, radioiodinated LPS containing a covalently linked, UV light-activated cross-linking group (125I-ASD-Re595 LPS). Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. These data support the contention that LPS is in close proximity to the three known proteins of its membrane receptor complex. Thus, LPS binds directly to each of the members of the tripartite LPS receptor complex.

Subfields: Immunology, Microbiology

View Paper: https://www.semanticscholar.org/paper/6126c93923f4e3a8cedf22c803040e298373096e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Shizuo Akira
2. R. Medzhitov
3. Jonathan C. Kagan
4. Taro Kawai
5. B. Beutler
6. K. Takeda
7. G. Barton
8. T. Kaisho

In Microbiology

1. Shizuo Akira
2. R. Medzhitov
3. K. Takeda
4. B. Beutler
5. T. Kaisho
6. Aly Karsan
7. S. Dauphinee
8. Jonathan C. Kagan

Citations in the corpus

• Toll-like receptors and innate immunity (2001, background): “; however, this interaction is clearly aided by CD14 and MD-2 (Ref”
• TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling (2020, background): “Both membrane-bound and soluble CD14 can transfer the LPS molecule to the TLR4/MD-2 complex [44, 46, 57].”
• Lipopolysaccharide signaling in endothelial cells (2006, background): “40 Formation of the complex between LPS and CD14 facilitates the transfer of LPS to the LPS receptor complex composed of TLR4 and MD2”
• Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics (2022, background): “In addition, several TLR4 co-receptors MD-2 and CD14 are indicated necessary for TLR4 recognition of LPS and TLR4 activation.(273) Airway epithelial cells and macrophages, both expressed TLR4 in the cell membrane, serve as the first line of host defense for the initial contact to P.”
• Toll-like receptors. (2003, background): “LPS stimulation is followed by increased physical proximity between CD14 and TLR4, suggesting that CD14 and TLR4 may interact in LPS signaling (42, 43).”
• How we detect microbes and respond to them: the Toll‐like receptors and their transducers (2003, background): “Genetic [31, 32] and biochemical [33] evidence of interaction between LPS and TLR4 has been presented.”
• CD14 controls the LPS-induced endocytosis of Toll-like Receptor 4 (2011, background): “186, 1027–1039. da Silva Correia, J., Soldau, K., Christen, U., Tobias, P.S., and Ulevitch, R.J. (2001).”
• Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “CD14 then transfers LPS to TLR4-bound MD-2, a process that dimerizes TLR4 and promotes signal transduction (58, 59).”