Class A scavenger receptor(SR-A) plays an important role in foam cell formation.However, the mechanism underlying the internalization of the receptor-ligand complexes remains unclear.The aim of the present study was to investigate the molecular mechanism to regulate SR-A-mediated intracellular lipid accumulation in macrophages A pull-clown assay was performed and glucoseregulated protein 78(GRP78) was identified to bind with the cytoplasmic domain of SR-A(CSR-A).Immunoprecipitation and artificially expressed protein binding assay demonstrated the direct specific binding of GRP78 with SR-A in cells.Indirect immunofluorescence assay and western blot analysis showed their co-localization in membrane and cytoplasm.Over-expression of GRP78 specifically inhibited SR-A-mediated uptake of fluorescent acetylated low-density lipoprotein, a specific ligand for SR-A, without altering cellular SR-A expression and binding ability, and significantly inhibited cholesterol ester accumulation in cells, which can be partly attributed to the suppression of c-Jun-NH2-terminal kinase signaling pathway.These results suggest that GRP78 may act as an inhibitor of SR-A-mediated internalization of modified low-density lipoprotein into macrophages(C) 2009 Elsevier Inc.All rights reserved. Class A scavenger receptor (SR-A) plays an important role in foam cell formation. However, the mechanism underlying the internalization of the receptor-ligand complexes remains unclear. The aim of the present study was to investigate the molecular mechanism to regulate SR- A-mediated intracellular lipid accumulation in macrophages A pull-clown assay was performed and glucose regulated protein 78 (GRP78) was identified to bind with the cytoplasmic domain of SR-A (CSR-A). Immunoprecipitation and artificially expressed protein binding assay demonstrated the direct specific binding of GRP78 with SR-A in cells. Indirect immunofluorescence assay and western blot analysis showed their co-localization in membrane and cytoplasm. Over-expression of GRP78 specifically inhibited SR-A-mediated uptake of fluorescent acetylated low-density lipoprotein, a specific ligand for SR-A, without altering cellular SR-A expression and binding ability, and significantly arrested cholesterol ester accumulation in cells, which can be partly attributed to the suppression of c-Jun-NH2-terminal kinase signaling pathway. These results suggest that GRP78 may act as an inhibitor of SR-A-mediated internalization of modified low-density lipoprotein into macrophages (C) 2009 Elsevier Inc.All rights reserved.