Glucose-regulated protein 78 inhibits scavenger receptor A-mediated internalization of acetylated low density lipoprotein.
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-down 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 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.
Ben
Jingjing
J
Institute of Reproductive Medicine, Nanjing Medical University, Nanjing, PR China.
Gao
Song
S
Zhu
Xudong
X
Zheng
Yuan
Y
Zhuang
Yan
Y
Bai
Hui
H
Xu
Yong
Y
Ji
Yong
Y
Sha
Jiahao
J
He
Zhigang
Z
Chen
Qi
Q
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D019084:Fluorescent Antibody Technique, Indirect; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D034622:RNA Interference; D051116:Receptors, Scavenger / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000873:Anthracenes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008077:Lipoproteins, LDL; D051116:Receptors, Scavenger; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases