CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior

Abstract

CD36 is a membrane glycoprotein present on platelets, mononuclear phagocytes, adipocytes, hepatocytes, myocytes, and some epithelia. On microvascular endothelial cells, CD36 is a receptor for thrombospondin-1 and related proteins and functions as a negative regulator of angiogenesis. On phagocytes, through its functions as a scavenger receptor recognizing specific oxidized phospholipids and lipoproteins, CD36 participates in internalization of apoptotic cells, certain bacterial and fungal pathogens, and modified low-density lipoproteins, thus contributing to inflammatory responses and atherothrombotic diseases. CD36 also binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption and possibly contributing to the pathogenesis of metabolic disorders, such as diabetes and obesity. On sensory cells, CD36 is involved in insect pheromone signaling and rodent fatty food preference. The signaling pathways downstream of CD36 involve ligand-dependent recruitment and activation of nonreceptor tyrosine kinases, specific mitogen-activated protein kinases, and the Vav family of guanine nucleotide exchange factors; modulation of focal adhesion constituents; and generation of intracellular reactive oxygen species. CD36 in many cells is localized in specialized cholesterol-rich membrane microdomains and may also interact with other membrane receptors, such as tetraspanins and integrins. Identification of the precise CD36 signaling pathways in specific cells elicited in response to specific ligands may yield novel targets for drug development.

Fig. 1

CD36 mediates cell-specific responses. (A) In endothelial cells, CD36 inhibits angiogenesis induced by growth factors, such as fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF), and promotes apoptosis. (B) In macrophages and monocytes, CD36 promotes inflammatory responses and phagocytosis. CD36 may interact with other receptors, such as integrins, TLRs, or tetraspanins, to mediate some of the responses. (C) In platelets, CD36 promotes activation, aggregation, and secretion. (D) In monocytes and macrophages, CD36 promotes the uptake of bioactive lipids, leading to activation of PPARγ transcriptional pathways. (E) In sensory cells, CD36 contributes to cellular responses in the mouth and gut to dietary fats in mammals (right) and to pheromone responses in Drosophila (left).

Fig. 2

Topology and domains of CD36. This ditopic transmembrane receptor resides in lipid raft membrane domains (shown shaded) and may interact with other cell surface receptors, such as integrins, tetraspanins, and TLRs (not shown). Ligand recognition may be modulated by phosphorylation of CD36 at Thr (92) (T). The extracellular domain contains three disulfide bridges (Cys²⁴³- Cys³¹¹, Cys²⁷²-Cys³³³, and Cys³¹³-Cys³²²), multiple glycosylation sites, and at least two separate ligand binding domains, one for proteins with thrombospondin repeat (TSR) domains and one for oxidized lipids. The N- and C-terminal tails contain paired palmitoylated cysteine residues. Tyr⁴⁶³ and Cys⁴⁶⁴ in the C-terminal tail are important for ligand binding and for interaction with downstream signaling molecules.