CD36 is a sensor of diacylglycerides (original) (raw)

Nature volume 433, pages 523–527 (2005)Cite this article

Abstract

Toll-like receptor 2 (TLR2) is required for the recognition of numerous molecular components of bacteria1,2,3,4,5,6,7,8, fungi9,10 and protozoa11. The breadth of the ligand repertoire seems unusual, even if one considers that TLR2 may form heteromers with TLRs 1 and 6 (ref. 12), and it is likely that additional proteins serve as adapters for TLR2 activation. Here we show that an _N_-ethyl-_N_-nitrosourea-induced nonsense mutation of Cd36 (oblivious) causes a recessive immunodeficiency phenotype in which macrophages are insensitive to the _R_-enantiomer of MALP-2 (a diacylated bacterial lipopeptide) and to lipoteichoic acid. Homozygous mice are hypersusceptible to Staphylococcus aureus infection. Cd36 obl macrophages readily detect _S_-MALP-2, PAM2CSK4, PAM3CSK4 and zymosan, revealing that some—but not all—TLR2 ligands are dependent on CD36. Already known as a receptor for endogenous molecules, CD36 is also a selective and nonredundant sensor of microbial diacylglycerides that signal via the TLR2/6 heterodimer.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Lien, E. et al. Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J. Biol. Chem. 274, 33419–33425 (1999)
    Article CAS Google Scholar
  2. Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11, 443–451 (1999)
    Article CAS Google Scholar
  3. Means, T. K. et al. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163, 3920–3927 (1999)
    CAS PubMed Google Scholar
  4. Takeuchi, O. et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933–940 (2001)
    Article CAS Google Scholar
  5. Takeuchi, O. et al. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10–14 (2002)
    Article CAS Google Scholar
  6. Morath, S., Stadelmaier, A., Geyer, A., Schmidt, R. R. & Hartung, T. Synthetic lipoteichoic acid from Staphylococcus aureus is a potent stimulus of cytokine release. J. Exp. Med. 195, 1635–1640 (2002)
    Article CAS Google Scholar
  7. Opitz, B. et al. Toll-like receptor-2 mediates Treponema glycolipid and lipoteichoic acid-induced NF-κB translocation. J. Biol. Chem. 276, 22041–22047 (2001)
    Article CAS Google Scholar
  8. Werts, C. et al. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nature Immunol. 2, 346–352 (2001)
    Article ADS CAS Google Scholar
  9. Gantner, B. N., Simmons, R. M., Canavera, S. J., Akira, S. & Underhill, D. M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1117 (2003)
    Article CAS Google Scholar
  10. Brown, G. D. et al. Dectin-1 mediates the biological effects of β-glucans. J. Exp. Med. 197, 1119–1124 (2003)
    Article CAS Google Scholar
  11. Campos, M. A. et al. Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J. Immunol. 167, 416–423 (2001)
    Article CAS Google Scholar
  12. Ozinsky, A. et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl Acad. Sci. USA 97, 13766–13771 (2000)
    Article ADS CAS Google Scholar
  13. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signaling. Nature 424, 743–748 (2003)
    Article ADS CAS Google Scholar
  14. Morr, M., Takeuchi, O., Akira, S., Simon, M. M. & Muhlradt, P. F. Differential recognition of structural details of bacterial lipopeptides by Toll-like receptors. Eur. J. Immunol. 32, 3337–3347 (2002)
    Article CAS Google Scholar
  15. Calvo, D., Dopazo, J. & Vega, M. A. The CD36, CLA-1 (CD36L1), and LIMPII (CD36L2) gene family: cellular distribution, chromosomal location, and genetic evolution. Genomics 25, 100–106 (1995)
    Article CAS Google Scholar
  16. Aitman, T. J. et al. Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats. Nature Genet. 21, 76–83 (1999)
    Article CAS Google Scholar
  17. Glazier, A. M., Scott, J. & Aitman, T. J. Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism. Mamm. Genome 13, 108–113 (2002)
    Article CAS Google Scholar
  18. Wright, S. D., Ramos, R. A., Tobias, P. S., Ulevitch, R. J. & Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249, 1431–1433 (1990)
    Article ADS CAS Google Scholar
  19. Gordon, S. Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927–930 (2002)
    Article CAS Google Scholar
  20. Rosenthal, R. S. & Dziarski, R. Isolation of peptidoglycan and soluble peptidoglycan fragments. Methods Enzymol. 235, 253–285 (1994)
    Article CAS Google Scholar
  21. Deininger, S. et al. Definition of structural prerequisites for lipoteichoic acid-inducible cytokine induction by synthetic derivatives. J. Immunol. 170, 4134–4138 (2003)
    Article CAS Google Scholar
  22. Kim, S. O., Ono, K. & Han, J. Apoptosis by pan-caspase inhibitors in lipopolysaccharide-activated macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L1095–L1105 (2001)
    Article CAS Google Scholar
  23. Hoebe, K., Du, X., Goode, J., Mann, N. & Beutler, B. Lps2: a new locus required for responses to lipopolysaccharide, revealed by germline mutagenesis and phenotypic screening. J. Endotoxin Res. 9, 250–255 (2003)
    Article CAS Google Scholar
  24. Poltorak, A. et al. Genetic and physical mapping of the Lps locus-identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol. Dis. 24, 340–355 (1998)
    Article CAS Google Scholar

Download references

Acknowledgements

This work was supported by the NIH.

Author information

Authors and Affiliations

  1. Department of Immunology, The Scripps Research Institute, La Jolla, California, 92037, USA
    Kasper Hoebe, Philippe Georgel, Sophie Rutschmann, Xin Du, Suzanne Mudd, Karine Crozat, Sosathya Sovath, Louis Shamel & Bruce Beutler
  2. EU Joint Research Centre, ECVAM, I-21020, Ispra, Italy
    Thomas Hartung
  3. Research Center Borstel, Leibniz-Center for Medicine and Biosciences, 23845, Borstel, Germany
    Ulrich Zähringer

Authors

  1. Kasper Hoebe
    You can also search for this author inPubMed Google Scholar
  2. Philippe Georgel
    You can also search for this author inPubMed Google Scholar
  3. Sophie Rutschmann
    You can also search for this author inPubMed Google Scholar
  4. Xin Du
    You can also search for this author inPubMed Google Scholar
  5. Suzanne Mudd
    You can also search for this author inPubMed Google Scholar
  6. Karine Crozat
    You can also search for this author inPubMed Google Scholar
  7. Sosathya Sovath
    You can also search for this author inPubMed Google Scholar
  8. Louis Shamel
    You can also search for this author inPubMed Google Scholar
  9. Thomas Hartung
    You can also search for this author inPubMed Google Scholar
  10. Ulrich Zähringer
    You can also search for this author inPubMed Google Scholar
  11. Bruce Beutler
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toBruce Beutler.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure IS 1-7

IS-1. Identification of LTA as the bioactive molecule in the peptidoglycan preparation that is discriminated by oblivious. IS-2. Molecular specificity of oblivious-mediated activation by lipopeptides, and dependency on TLR2. IS-3. The oblivious mutation only partially blocks activation of MAP kinases and I B degradation when cells are stimulated with LTA (a) or racemic MALP-2 (b). IS-4. Spontaneous eye infection in oblivious mice. IS-5. Western blot analysis of CD36 in cell extract or supernatant from wildtype or oblivious mice cultured for 24 h in vitro. IS-6. CD36 augments the response to LTA and R-MALP-2. IS-7. Unrooted tree depicting phylogeny of the CD36 family. (PDF 3248 kb)

Supplementary Legends IS 1-7 (DOC 26 kb)

Rights and permissions

About this article

Cite this article

Hoebe, K., Georgel, P., Rutschmann, S. et al. CD36 is a sensor of diacylglycerides.Nature 433, 523–527 (2005). https://doi.org/10.1038/nature03253

Download citation

This article is cited by