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CD36 is a sensor of diacylglycerides

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. Cd36obl 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.

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Figure 1: Oblivious specifically reduces TNF production in response to Staphylococcus-derived peptidoglycan and synthetic MALP-2.
Figure 2: Oblivious homozygous mutant mice are unable to contain Gram-positive S. aureus infections.
Figure 3: Confinement of the obl critical region and identification of the obl mutation.
Figure 4: A nonsense mutation in CD36 is responsible for the oblivious phenotype.

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Acknowledgements

This work was supported by the NIH.

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Correspondence to Bruce Beutler.

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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)

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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

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