CD36 is a sensor of diacylglycerides.
Toll-like receptor 2 (TLR2) is required for the recognition of numerous molecular components of bacteria, fungi and protozoa. 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, PAM(2)CSK(4), PAM(3)CSK(4) 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.
Hoebe
Kasper
K
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Georgel
Philippe
P
Rutschmann
Sophie
S
Du
Xin
X
Mudd
Suzanne
S
Crozat
Karine
K
Sovath
Sosathya
S
Shamel
Louis
L
Hartung
Thomas
T
Zähringer
Ulrich
U
Beutler
Bruce
B
D000375:Aging / Q000502:physiology; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D019281:Dimerization; D005038:Ethylnitrosourea / Q000494:pharmacology; D017353:Gene Deletion; D005989:Glycerides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000139:chemically induced; D055666:Lipopeptides; D008562:Membrane Glycoproteins / Q000819:agonists / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010457:Peptidoglycan / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000819:agonists / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000737:chemistry / Q000502:physiology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015054:Zymosan / Q000494:pharmacology
D018955:CD36 Antigens; D005989:Glycerides; D055666:Lipopeptides; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; C106335:macrophage stimulatory lipopeptide 2; D005038:Ethylnitrosourea