Dysfunction of three CD36 variants is due to impaired glycosylation and trafficking

CD36 deficiency is characterized by the loss of CD36 due to genetic mutations. Clinical studies have associated CD36 deficiency with hyperlipidemia, insulin resistance, and cardiomyopathy. However, the structural and functional effects of human CD36 variants remain poorly understood. P90S is a causative mutation of CD36 deficiency while E123K and S127L are of unknown significance and typically found in malarial endemic regions. Despite their variable phenotypes, they are all located in the same structural region of CD36. In this study, we expressed these three naturally occurring human CD36 variants in HEK293 cells and found that all variants exhibited impaired oxLDL binding and uptake that was associated with reduced expression, shortened half-lives, and altered glycan processing, consistent with defects in receptor maturation. Inhibition of proteasomal or lysosomal pathways did not restore variant stability, suggesting that reduced receptor abundance is not mediated by a single canonical degradation pathway. All variants exhibited reduced membrane accumulation without enrichment in specific intracellular compartments, indicating impaired trafficking rather than selective retention. These findings provide mechanistic insight into the regulation of human CD36 expression, maturation, and trafficking, and the functional consequences of genetic variation.