International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 91 - THE NONSENSE ALLELE OBLIVIOUS REVEALS A SENSOR OF DI‑ACYLGLYCERIDES ACTING IN CONJUNCTION WITH TLR2 AND TLR6

Hoebe K 1, Georgel P 1, Rutschmann S 1, Du X 1, Tabeta K 1, Mudd S 1, Sovath S 1, Shamel L 1, Hartung T 2, Zahringer U 3, Beutler B 1

1 The Scripps Research Institue, La Jolla, United States, 2 Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany, 3 Research Center Borstel, Leipniz-center for Medicine and Bioscience, Borstel, Germany

The mammalian Toll-like receptors (TLRs) activate cells of the innate immune system when stimulated by diverse ligands of microbial origin.  In some instances, these ligands are directly engaged by the TLRs; however, this is not necessarily true in all cases. TLR2 recognizes multiple, structurally disparate microbial ligands, consistent with a requirement for co-receptors in ligand binding.  Using N-ethyl-N-nitrosourea (ENU), we generated the recessive immunodeficiency phenotype oblivious, in which macrophages show diminished awareness of the S-enantiomer of the di-acylated bacterial lipopeptide MALP-2 and lipoteichoic acid (LTA), together with an increased susceptibility to Staphylococcus aureus infection.  Oblivious macrophages readily detect the tri-acylated bacterial lipopeptide PAM3CSK4 as well as zymosan, revealing that some TLR2 ligands are activated via an Oblivious-independent pathway.  The gene responsible for the oblivious phenotype has been positionally cloned and was proven to result from a nonsense mutation in Cd36, which encodes a double-spanning cell surface protein expressed by murine myeloid cells.  A receptor for endogenous molecules including fatty acids, thrombospondin, oxidized LDL, and b -amyloid, CD36 is also a selective and nonredundant sensor of microbial di-acylglycerides, and makes an important contribution to anti-bacterial defense.  We propose that CD36 may initiate TLR2-mediated inflammatory responses through recognition of both endogenous and exogenous ligands.

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