Work

Acid sphingomyelinase recruits palmitoylated CD36 to membrane rafts and enhances lipid uptake

Year: 2025

Type: article

Abstract: CD36 palmitoylation increases its membrane localization and is required for CD36-mediated uptake of oxidized low-density lipoprotein (oxLDL). Acid sphingomyelinase (ASMase) is transported to the plasma membrane, where it promotes lipid raft clustering, facilitating membrane protein anchoring for biological functions. We investigated the effects of oxLDL on CD36 palmitoylation and explored the role of ASMase in CD36 membrane translocation. We found that oxLDL increased CD36 palmitoylation and drives its intracellular trafficking from the endoplasmic reticulum to the plasma membrane lipid rafts in macrophages. Affinity purification followed by mass spectrometry analysis identified CD36 bound to ASMase in the plasma membrane. The CD36/ASMase binding was enhanced by oxLDL treatment. Genetic ablation and pharmacological inhibition of ASMase reduced CD36 recruitment to lipid rafts and inhibited CD36 intracellular signaling and lipid uptake. Moreover, inhibiting Sortilin to block ASMase intracellular trafficking and reduce membrane ASMase also caused a sharp decrease in the amount of membrane CD36. In addition, ASMase overexpression dramatically promoted palmitoylated CD36 membrane localization but not CD36 without palmitoylation, in which the modification was inhibited by 2-bromopalmitate (2-BP) treatment or point mutation at the palmitoylation site. Moreover, ASMase knockout inhibited CD36 membrane recruitment both in peritoneal macrophages and in the aorta, and attenuated lipid accumulation in atherosclerotic plaques in mice. Finally, we found oxLDL activated extracellular signal-regulated kinase1/2 (ERK1/2)/specificity protein (SP1) signaling, upregulating ASMase transcription and promoting sphingomyelin catabolism. Therefore, these data demonstrate that ASMase expression induced by oxLDL is required for palmitoylated CD36 membrane translocation during foam cell formation in macrophages.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2025.110213