SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.
SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.
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DOI：
10.7554/elife.00444
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发表时间：
2013-04-09
期刊：
影响因子：
7.7
通讯作者：
Ginsburg D
中科院分区：
文献类型：
--
作者：
Chen XW;Wang H;Bajaj K;Zhang P;Meng ZX;Ma D;Bai Y;Liu HH;Adams E;Baines A;Yu G;Sartor MA;Zhang B;Yi Z;Lin J;Young SG;Schekman R;Ginsburg D
真核细胞的分泌途径将货物蛋白包装到COPII包被的小泡中，从内质网(ER)运输到高尔基体。我们现在报告COPII组分SEC24A的完全遗传缺陷与小鼠的正常生存和发育是兼容的，尽管SEC24在COPII囊泡形成和货物募集中起着重要作用。然而，这些动物表现出显著的血浆胆固醇降低，APOE和LdlR突变与SEC24A上位，表明一种受体介导的脂蛋白清除机制。与这些数据一致，肝脏LDLR水平在SEC24A缺陷细胞中上调，这是由于LDLR的负调控因子PCSK9对SEC24A有效退出内质网的特定依赖。我们的发现还发现SEC24A和SEC24B之间在货物选择性方面存在部分重叠，这表明在COPII囊泡中招募分泌蛋白方面存在以前未被认识到的异质性，这种异质性延伸到可溶性和跨膜货物。DOI：http://dx.doi.org/10.7554/eLife.00444.001内质网(ER)是真核细胞内执行多种功能的结构。它可以分为两个区域：粗糙的内质网表面覆盖着制造各种蛋白质的核糖体，而光滑的内质网参与脂肪合成和碳水化合物代谢等活动。由附着在粗面内质网上的核糖体合成的蛋白质通常被转移到细胞内的另一个结构，即高尔基体，在那里它们经过进一步的处理和包装，然后被分泌或运输到细胞内的另一个位置。蛋白质通过被外壳蛋白复合体II(COPII)覆盖的小泡从内质网运送到高尔基体。该复合体由内衣和外衣组成，每一层主要由两种不同的SEC蛋白组装而成：SEC23/SEC24蛋白异二聚体形成COPII囊泡的内衣，在将适当的蛋白质货物募集到运输囊泡中起关键作用，而SEC13/SEC31蛋白异构体形成外衣，通常负责调节囊泡的大小和硬度。先前的工作发现，哺乳动物，包括人类和老鼠，拥有几个SEC蛋白基因的多个副本，包括两个副本的SEC23和四个副本的SEC24。SEC23的两个拷贝都来自同一个祖先基因，而SEC24的所有四个拷贝都来自不同的祖先基因，这些拷贝的存在潜在地扩大了小泡可能具有的特性范围。对每种SEC蛋白的作用的洞察来自于与SEC突变体的工作。例如，SEC23A的一个突变被发现会导致人类骨骼异常。这里，Chen等人。报道了实验结果，实验结果表明，SEC24A基因失活的小鼠可以正常发育。然而，这些小鼠的血浆胆固醇水平下降了45%，因为它们无法招募和运输一种名为PCSK9的分泌蛋白，PCSK9是血液胆固醇水平的关键调节因子。Chen等人的工作。揭示了在COPII囊泡中招募分泌蛋白的以前未被意识到的复杂性，并表明SEC蛋白的各种组合影响着被选择运输到高尔基体的蛋白。这项工作还将SEC24A确定为降低血浆胆固醇的潜在治疗靶点，这一发现可能会引起研究心脏病和其他因高胆固醇而加剧的疾病的研究人员的兴趣。DOI：http://dx.doi.org/10.7554/eLife.00444.002
The secretory pathway of eukaryotic cells packages cargo proteins into COPII-coated vesicles for transport from the endoplasmic reticulum (ER) to the Golgi. We now report that complete genetic deficiency for the COPII component SEC24A is compatible with normal survival and development in the mouse, despite the fundamental role of SEC24 in COPII vesicle formation and cargo recruitment. However, these animals exhibit markedly reduced plasma cholesterol, with mutations in Apoe and Ldlr epistatic to Sec24a, suggesting a receptor-mediated lipoprotein clearance mechanism. Consistent with these data, hepatic LDLR levels are up-regulated in SEC24A-deficient cells as a consequence of specific dependence of PCSK9, a negative regulator of LDLR, on SEC24A for efficient exit from the ER. Our findings also identify partial overlap in cargo selectivity between SEC24A and SEC24B, suggesting a previously unappreciated heterogeneity in the recruitment of secretory proteins to the COPII vesicles that extends to soluble as well as trans-membrane cargoes. DOI: http://dx.doi.org/10.7554/eLife.00444.001 The endoplasmic reticulum (ER) is a structure that performs a variety of functions within eukaryotic cells. It can be divided into two regions: the surface of the rough ER is coated with ribosomes that manufacture various proteins, while the smooth ER is involved in activities such as lipid synthesis and carbohydrate metabolism. Proteins synthesized by the ribosomes attached to the rough ER are generally transferred to another structure within the cell, the Golgi apparatus, where they undergo further processing and packaging before being secreted or transported to another location within the cell. Proteins are shuttled from the ER to the Golgi apparatus by vesicles covered with coat protein complex II (COPII). This complex is composed of an inner and outer coat, each of which is assembled primarily with two different SEC proteins: the SEC23/SEC24 protein heterodimer forms the inner coat of the COPII vesicle, and plays a key role in recruiting the appropriate protein cargos to the transport vesicle, while the SEC13/SEC31 protein heterotetramer forms the outer coat and is generally responsible for regulating vesicle size and rigidity. Previous work found that mammals, including humans and mice, harbor multiple copies of several SEC protein genes, including two copies of SEC23 and four copies of SEC24. Both copies of SEC23 are derived from the same ancestral gene, and all four copies of SEC24 are derived from a different ancestral gene, and the availability of these copies potentially expands the range of properties that the vesicles can have. Insight into the roles of each SEC protein has come from work with SEC mutants. For example, a mutation in SEC23A was found to cause skeletal abnormalities in humans. Here, Chen et al. report the results of experiments which showed that mice with an inactive Sec24a gene could develop normally. However, these mice experienced a 45% reduction in their plasma cholesterol levels because they were not able to recruit and transport a secretory protein called PCSK9, which is a critical regulator of blood cholesterol levels. The work of Chen et al. reveals a previously unappreciated complexity in the recruitment of secretory proteins to the COPII vesicle and suggests that the various combinations of SEC proteins influence the proteins selected for transport to the Golgi apparatus. The work also identifies Sec24a as a potential therapeutic target for the reduction of plasma cholesterol, a finding that could be of interest to researchers working on heart disease and other conditions exacerbated by high cholesterol. DOI: http://dx.doi.org/10.7554/eLife.00444.002