Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100.
Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100.
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DOI：
10.1161/circresaha.117.311240
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发表时间：
2018-02-16
影响因子：
20.1
通讯作者：
Fisher EA
中科院分区：
文献类型：
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作者：
Amengual J;Guo L;Strong A;Madrigal-Matute J;Wang H;Kaushik S;Brodsky JL;Rader DJ;Cuervo AM;Fisher EA
全基因组关联研究发现SORT 1位点附近的单核苷酸多态性（SNP）与血浆低密度脂蛋白胆固醇（LDL-C）水平降低以及预防动脉粥样硬化性心血管疾病和心肌梗死密切相关。SORT 1 SNP基因座的次要等位基因在SORT 1启动子中产生了一个假定的C/EBPα结合位点，从而使富含该转录因子的肝脏中分拣蛋白的表达增加了12倍。我们之前在小鼠中的研究表明，血浆LDL-C及其主要蛋白组分载脂蛋白B（apoB）降低，SORT 1表达增加，体外研究表明分拣蛋白促进了与LDL前体极低密度脂蛋白（VLDL）相关的apoB的分泌前溶酶体降解。直接确定SORT 1过表达导致apoB降解，并确定其减少肝脏apoB和VLDL分泌的机制，从而有助于了解低LDL-C水平的临床表型。脉冲追踪研究直接确定SORT 1过表达导致apoB降解。如上所述，先前的工作暗示了溶酶体在这种降解中的作用。通过在体外和体内的研究，我们现在证明，分拣蛋白介导的途径apoB的溶酶体是非常规的，并与自噬交叉。分拣蛋白表达的增加使更多的apoB从分泌中转移，两种蛋白质都运输到囊泡中的内体区室，与自噬体融合形成两性体。两性体然后与溶酶体合并。此外，我们表明，分拣蛋白本身是一个调节器的自噬和它的活动是缩放的载脂蛋白B的合成水平。这些结果强烈表明，依赖于自噬的非常规溶酶体靶向过程降解了由分拣蛋白从分泌途径转移的apoB，并提供了一种有助于SORT 1过表达个体中发现的LDL-C降低的机制。
Genome-Wide Association Studies identified single nucleotide polymorphisms (SNPs) near the SORT1 locus strongly associated with decreased plasma low-density lipoprotein cholesterol (LDL-C) levels and protection from atherosclerotic cardiovascular disease and myocardial infarction. The minor allele of the causal SORT1 SNP locus creates a putative C/EBPα binding site in the SORT1 promoter, thereby increasing sortilin expression by 12-fold in liver, which is rich in this transcription factor. Our previous studies in mice have showed reductions in plasma LDL-C and its principal protein component, apolipoprotein B (apoB) with increased SORT1 expression, and in vitro studies suggested that sortilin promoted the presecretory lysosomal degradation of apoB associated with the LDL precursor, very-low density lipoprotein (VLDL). To determine directly that SORT1 overexpression results in apoB degradation and to identify the mechanisms by which this reduces apoB and VLDL secretion by the liver, thereby contributing to understanding the clinical phenotype of lower LDL-C levels. Pulse-chase studies directly established that SORT1 overexpression results in apoB degradation. As noted above, previous work implicated a role for lysosomes in this degradation. Through in vitro and in vivo studies, we now demonstrate that the sortilin-mediated route of apoB to lysosomes is unconventional and intersects with autophagy. Increased expression of sortilin diverts more apoB away from secretion, with both proteins trafficking to the endosomal compartment in vesicles that fuse with autophagosomes to form amphisomes. The amphisomes then merge with lysosomes. Furthermore, we show that sortilin itself is a regulator of autophagy and that its activity is scaled to the level of apoB synthesis. These results strongly suggest that an unconventional lysosomal targeting process dependent on autophagy degrades apoB that was diverted from the secretory pathway by sortilin, and provide a mechanism contributing to the reduced LDL-C found in individuals with SORT1 overexpression.