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Gene Review

LY96  -  lymphocyte antigen 96

Homo sapiens

Synonyms: ESOP-1, ESOP1, Ly-96, Lymphocyte antigen 96, MD-2, ...
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Disease relevance of LY96


High impact information on LY96


Chemical compound and disease context of LY96

  • However, purified LOS from diverse strains of Neisseria (both N. meningitidis and N. gonorrhoeae) caused widely variant levels of IL-8 promoter induction in cells expressing MD2 that correlated with the production of TNF from THP-1 cells [6].

Biological context of LY96

  • These observations demonstrate that hMD-2 undergoes N-linked glycosylation at Asn(26) and Asn(114), and that these glycosylations are crucial for TLR4-mediated signal transduction of LPS [7].
  • Mutation of either one of two potential glycosylation sites (Asn(26) and Asn(114)) of MD-2 resulted in the disappearance of the slowest mobility form, and only the fastest form was detected in hMD-2 carrying mutations at both Asn(26) and Asn(114) [7].
  • Additional transfection with MD-2 did not affect stimulation of these cells by LTA [8].
  • Here we propose two possible mechanisms for LPS recognition and signalling that take into account both the structural information available for TLR4 and MD-2, and the determinants of endotoxicity, namely, the acylation and phosphorylation patterns of LPS [9].
  • Unlike LPS, Mtb-induced macrophage activation was not augmented by overexpression of ectopic MD-2 [10].

Anatomical context of LY96


Associations of LY96 with chemical compounds


Physical interactions of LY96

  • Interaction of soluble form of recombinant extracellular TLR4 domain with MD-2 enables lipopolysaccharide binding and attenuates TLR4-mediated signaling [19].
  • Biochemical and visual studies shown here demonstrate that the role of CD14 in signal transduction is to enhance LPS binding to MD-2, although its expression is not essential for cellular activation [20].
  • In order to mediate cellular response to lipopolysaccharide (LPS), Toll-like receptor (TLR) 4 must interact with MD-2, a secreted protein [21].
  • Soluble G56R MD-2 showed markedly reduced LPS binding that was to a large degree rescued by TLR4 coexpression or presence of TLR4 ectodomain [22].

Regulatory relationships of LY96

  • Little is known, however, as to whether MD-2 directly regulates LPS recognition by TLR4 [23].
  • IFN-gamma positively regulated MD-2 promoter activity in IEC [16].
  • An endotoxin-mutant (F126A) MD-2 complex that does not activate cells expressing TLR4 alone potently activates cells expressing mCD14, MD-2, and TLR4 by transferring endotoxin to mCD14, which then transfers endotoxin to endogenous wild-type MD-2.TLR4 [24].

Other interactions of LY96


Analytical, diagnostic and therapeutic context of LY96


  1. MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components. Dziarski, R., Wang, Q., Miyake, K., Kirschning, C.J., Gupta, D. J. Immunol. (2001) [Pubmed]
  2. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Paik, Y.H., Schwabe, R.F., Bataller, R., Russo, M.P., Jobin, C., Brenner, D.A. Hepatology (2003) [Pubmed]
  3. MD-2 mediates the ability of tetra-acylated and penta-acylated lipopolysaccharides to antagonize Escherichia coli lipopolysaccharide at the TLR4 signaling complex. Coats, S.R., Pham, T.T., Bainbridge, B.W., Reife, R.A., Darveau, R.P. J. Immunol. (2005) [Pubmed]
  4. Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance. Cario, E., Golenbock, D.T., Visintin, A., Rünzi, M., Gerken, G., Podolsky, D.K. J. Immunol. (2006) [Pubmed]
  5. Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. Schromm, A.B., Lien, E., Henneke, P., Chow, J.C., Yoshimura, A., Heine, H., Latz, E., Monks, B.G., Schwartz, D.A., Miyake, K., Golenbock, D.T. J. Exp. Med. (2001) [Pubmed]
  6. Activation of toll-like receptor 2 (TLR2) and TLR4/MD2 by Neisseria is independent of capsule and lipooligosaccharide (LOS) sialylation but varies widely among LOS from different strains. Pridmore, A.C., Jarvis, G.A., John, C.M., Jack, D.L., Dower, S.K., Read, R.C. Infect. Immun. (2003) [Pubmed]
  7. N-linked glycosylations at Asn(26) and Asn(114) of human MD-2 are required for toll-like receptor 4-mediated activation of NF-kappaB by lipopolysaccharide. Ohnishi, T., Muroi, M., Tanamoto, K. J. Immunol. (2001) [Pubmed]
  8. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. Schröder, N.W., Morath, S., Alexander, C., Hamann, L., Hartung, T., Zähringer, U., Göbel, U.B., Weber, J.R., Schumann, R.R. J. Biol. Chem. (2003) [Pubmed]
  9. MD-2: the Toll 'gatekeeper' in endotoxin signalling. Gangloff, M., Gay, N.J. Trends Biochem. Sci. (2004) [Pubmed]
  10. Differential effects of a Toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses. Means, T.K., Jones, B.W., Schromm, A.B., Shurtleff, B.A., Smith, J.A., Keane, J., Golenbock, D.T., Vogel, S.N., Fenton, M.J. J. Immunol. (2001) [Pubmed]
  11. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. Latz, E., Visintin, A., Lien, E., Fitzgerald, K.A., Monks, B.G., Kurt-Jones, E.A., Golenbock, D.T., Espevik, T. J. Biol. Chem. (2002) [Pubmed]
  12. Human Conjunctival Epithelial Cells Lack Lipopolysaccharide Responsiveness Due to Deficient Expression of MD2 but Respond After Interferon-gamma Priming or Soluble MD2 Supplementation. Talreja, J., Dileepan, K., Puri, S., Kabir, M.H., Segal, D.M., Stechschulte, D.J., Dileepan, K.N. Inflammation (2005) [Pubmed]
  13. Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4. Visintin, A., Mazzoni, A., Spitzer, J.A., Segal, D.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  14. A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2. Pridmore, A.C., Wyllie, D.H., Abdillahi, F., Steeghs, L., van der Ley , P., Dower, S.K., Read, R.C. J. Infect. Dis. (2001) [Pubmed]
  15. The role of disulfide bonds in the assembly and function of MD-2. Mullen, G.E., Kennedy, M.N., Visintin, A., Mazzoni, A., Leifer, C.A., Davies, D.R., Segal, D.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  16. TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. Abreu, M.T., Arnold, E.T., Thomas, L.S., Gonsky, R., Zhou, Y., Hu, B., Arditi, M. J. Biol. Chem. (2002) [Pubmed]
  17. Expression of a Porphyromonas gingivalis lipid A palmitylacyltransferase in Escherichia coli yields a chimeric lipid A with altered ability to stimulate interleukin-8 secretion. Bainbridge, B.W., Coats, S.R., Pham, T.T., Reife, R.A., Darveau, R.P. Cell. Microbiol. (2006) [Pubmed]
  18. Comparison of vecuronium with ORG 9487 and their interaction. Schiere, S., van den Broek, L., Proost, J.H., Molenbuur, B., Wierda, J.M. Canadian journal of anaesthesia = Journal canadien d'anesthésie. (1997) [Pubmed]
  19. Interaction of soluble form of recombinant extracellular TLR4 domain with MD-2 enables lipopolysaccharide binding and attenuates TLR4-mediated signaling. Hyakushima, N., Mitsuzawa, H., Nishitani, C., Sano, H., Kuronuma, K., Konishi, M., Himi, T., Miyake, K., Kuroki, Y. J. Immunol. (2004) [Pubmed]
  20. Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction. Visintin, A., Latz, E., Monks, B.G., Espevik, T., Golenbock, D.T. J. Biol. Chem. (2003) [Pubmed]
  21. Monomeric recombinant MD-2 binds toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness. Re, F., Strominger, J.L. J. Biol. Chem. (2002) [Pubmed]
  22. Functional activity of MD-2 polymorphic variant is significantly different in soluble and TLR4-bound forms: decreased endotoxin binding by G56R MD-2 and its rescue by TLR4 ectodomain. Vasl, J., Prohinar, P., Gioannini, T.L., Weiss, J.P., Jerala, R. J. Immunol. (2008) [Pubmed]
  23. Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition. Akashi, S., Nagai, Y., Ogata, H., Oikawa, M., Fukase, K., Kusumoto, S., Kawasaki, K., Nishijima, M., Hayashi, S., Kimoto, M., Miyake, K. Int. Immunol. (2001) [Pubmed]
  24. Transfer of monomeric endotoxin from MD-2 to CD14: characterization and functional consequences. Teghanemt, A., Prohinar, P., Gioannini, T.L., Weiss, J.P. J. Biol. Chem. (2007) [Pubmed]
  25. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Ahmad-Nejad, P., Häcker, H., Rutz, M., Bauer, S., Vabulas, R.M., Wagner, H. Eur. J. Immunol. (2002) [Pubmed]
  26. Lipopolysaccharide induces CD25-positive, IL-10-producing lymphocytes without secretion of proinflammatory cytokines in the human colon: low MD-2 mRNA expression in colonic macrophages. Shirai, Y., Hashimoto, M., Kato, R., Kawamura, Y.I., Kirikae, T., Yano, H., Takashima, J., Kirihara, Y., Saito, Y., Fujino, M.A., Dohi, T. J. Clin. Immunol. (2004) [Pubmed]
  27. The Toll-like receptor 4 region Glu24-Pro34 is critical for interaction with MD-2. Nishitani, C., Mitsuzawa, H., Hyakushima, N., Sano, H., Matsushima, N., Kuroki, Y. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  28. Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor alpha. Ruemmele, F.M., Beaulieu, J.F., Dionne, S., Levy, E., Seidman, E.G., Cerf-Bensussan, N., Lentze, M.J. Gut (2002) [Pubmed]
  29. Expression of toll-like receptor 4 and its associated lipopolysaccharide receptor complex by resident antigen-presenting cells in the human uvea. Chang, J.H., McCluskey, P., Wakefield, D. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  30. Toll-like receptor mRNA levels in alveolar macrophages after inhalation of endotoxin. Maris, N.A., Dessing, M.C., de Vos, A.F., Bresser, P., van der Zee, J.S., Jansen, H.M., Spek, C.A., van der Poll, T. Eur. Respir. J. (2006) [Pubmed]
  31. Lipopolysaccharide (LPS) regulates TLR4 signal transduction in nasopharynx epithelial cell line 5-8F via NFkappaB and MAPKs signaling pathways. Yang, Y., Zhou, H., Yang, Y., Li, W., Zhou, M., Zeng, Z., Xiong, W., Wu, M., Huang, H., Zhou, Y., Peng, C., Huang, C., Li, X., Li, G. Mol. Immunol. (2007) [Pubmed]
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