[HTML][HTML] A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I

N Wang, W Chen, P Linsel-Nitschke… - The Journal of …, 2003 - Am Soc Clin Investig
N Wang, W Chen, P Linsel-Nitschke, LO Martinez, B Agerholm-Larsen, DL Silver, AR Tall
The Journal of clinical investigation, 2003Am Soc Clin Investig
Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic
lesions. ABCA1, the defective molecule in Tangier disease, mediates the efflux of
phospholipids and cholesterol from cells to apoA-I, reversing foam cell formation. In ABCA1,
we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST
sequence) that enhances the degradation of ABCA1 by calpain protease and thereby
controls the cell surface concentration and cholesterol efflux activity of ABCA1. In an …
Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic lesions. ABCA1, the defective molecule in Tangier disease, mediates the efflux of phospholipids and cholesterol from cells to apoA-I, reversing foam cell formation. In ABCA1, we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST sequence) that enhances the degradation of ABCA1 by calpain protease and thereby controls the cell surface concentration and cholesterol efflux activity of ABCA1. In an apparent positive feedback loop, apoA-I binds ABCA1, promotes lipid efflux, inhibits calpain degradation, and leads to increased levels of ABCA1. ApoA-I infusion also increases ABCA1 in vivo. These studies reveal a novel mode of regulation of ABCA1 by PEST sequence–mediated calpain proteolysis that appears to be reversed by apolipoprotein-mediated phospholipid efflux. Inhibition of ABCA1 degradation by calpain could represent a novel therapeutic approach to increasing macrophage cholesterol efflux and decreasing atherosclerosis.
The Journal of Clinical Investigation