CD36 Its function as scavenger receptor revisited

CD36 is a member of the scavenger receptor type B family, which encompasses three paralogous proteins encoded by both the mouse and human genomes [59]. Each of these proteins has two membrane-spanning domains, one at the N-termi-nus and the other near the C-terminus of the polypeptide chain. In the case of CD36, the protein is anchored in caveolae or lipid rafts, and most of the amino acid chain projects into the extracellular space (few residues, if any, project into the cytoplasm). Several functions have been assigned to CD36 (also known as platelet glycoprotein IV (GPIV) [60], glycoprotein IIIB [61], PAS IV [62] on the basis of bio-

Diacylaled lipopeptides

Diacylaled lipopeptides

IRAK4

IRAK4

Figure 3

Recognition of bacterial-derived lipopeptides and/or peptidoglycan through TLRs and/or cytosolic Nod proteins. Bacterial lipopeptides are able to activate TLR2 directly, or het-erodimers consisting of TLR1/2 or TLR2/6, resulting in the activation of the MyD88-depen-dent pathway with activation of NF-kB. The scavenger receptor CD36 acts as a sensor of dia-cylglycerides such as lipoteichoic acid (LTA) and MALP-2 in concert with the TLR2/6 het-erodimer. Alternatively, peptidoglycan-derivatives such as muramyl dipeptide (MDP) and GM-triDAP activate NF-kB through activation of Nod1 or Nod2 proteins.

chemical and genetic data), and specific molecular domains - mostly within the N-terminal quarter of the protein - have been identified as important for several of these functions (reviewed in [63]). CD36 has been implicated as a receptor for endogenous molecules, including thrombospondin A and oxidized LDL [64]. Furthermore, it has been implicated in the cytoadhesion of plasmodium-infected ery-throcytes [65], through non-opsonic phagocytosis triggered by PfEMP-1, a protein encoded by Plasmodium falciparum [66, 67]. In addition, CD36 was shown to be involved in the removal of outer segments by retinal pigmented epithelium [68].

However, the recognition of defined molecules of eubacterial origin and the direct link to receptors of the innate immune system appears to be a major (and until recently unrecognized) role for CD36. At present, it is possible, though uncertain, that the two remaining mammalian CD36 family members operate in an analogous fashion.

LTA is characteristic of nearly all Gram-positive bacteria, and di-acylated lipopeptides are made by a great number of Gram-positive and Gram-negative organisms. The sensing function of CD36 is therefore likely to be exercised quite broadly. In human populations, CD36 deficiency caused by structural mutations of the CD36 gene [69-71] may affect platelets and monocytes (type I) or platelets alone (type II). The latter defect occurs at population frequency between 3% and 11% in Japan; the former is somewhat less common, but is by no means rare. A high frequency of nonsense and missense mutations of CD36 has been observed in African populations as well [72]. It may be assumed that CD36 deficiency is likely to cause some degree of selective immunocompromise in humans as it clearly does in mice, likely balanced by a phenotypic advantage yet unknown.

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