A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I.
A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I.
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DOI：
10.1172/jci16808
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Nan Wang;Wengen Chen;P. Linsel-Nitschke;L. Martinez;B. Agerholm-Larsen;D. Silver;A. Tall
中科院分区：
文献类型：
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作者：
Nan Wang;Wengen Chen;P. Linsel-Nitschke;L. Martinez;B. Agerholm-Larsen;D. Silver;A. Tall
载胆固醇的巨噬泡沫细胞是动脉粥样硬化病变的中心成分。ABCA 1是丹吉尔病中的缺陷分子，介导磷脂和胆固醇从细胞流出至apoA-I，逆转泡沫细胞形成。在ABCA 1中，我们鉴定了富含脯氨酸、谷氨酸、丝氨酸和苏氨酸的序列（PEST序列），其增强了钙蛋白酶对ABCA 1的降解，从而控制了ABCA 1的细胞表面浓度和胆固醇流出活性。在一个明显的正反馈回路中，apoA-I结合ABCA 1，促进脂质流出，抑制钙蛋白酶降解，并导致ABCA 1水平升高。ApoA-I输注也增加体内ABCA 1。这些研究揭示了一种新的模式的调节ABCA 1的PEST序列介导的钙蛋白酶蛋白水解，似乎是逆转载脂蛋白介导的磷脂流出。钙蛋白酶抑制ABCA 1降解可能代表一种新的治疗方法，增加巨噬细胞胆固醇流出和减少动脉粥样硬化。
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.