Toxin entry: retrograde transport through the secretory pathway.
Toxin entry: retrograde transport through the secretory pathway.
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DOI：
10.1083/jcb.140.4.733
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发表时间：
1998-02-23
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真核细胞中分泌蛋白的合成、分离、胞内转运和胞外输出现在已经很清楚。合成开始于随后附着于ER的游离胞质核糖体，导致新生蛋白质共翻译释放到ER腔中。靶向信号和介导易位步骤的胞质和ER膜组分已被广泛表征和综述（例如，参见29）。ER腔含有一系列负责修饰新合成多肽并确保正确折叠成生物活性构象的常驻蛋白（9）。分泌需要将蛋白质从ER经由高尔基体堆叠和TGN转运至分泌囊泡，分泌囊泡最终与质膜融合以完成蛋白质输出。Palade及其同事阐明了分泌途径（24）。蛋白质在分泌途径的各个隔室之间的转运是由载体囊泡介导的，载体囊泡从一个隔室出芽并与下一个隔室融合。再一次，许多细胞成分，所需的，并调节，囊泡运输已被确定，和细胞质蛋白质外壳驱动的各个运输步骤的机制，现在正在出现（31）。一段时间以来，人们已经认识到分泌途径至少部分可逆。例如，需要从高尔基体到ER的逆行囊泡运输来回收已经从该隔室逃逸的驻留ER蛋白（25），并且内吞作用可以将蛋白质从细胞表面运输到TGN（2），TGN是分泌和内吞途径会聚的细胞位置（31）。ER驻留蛋白含有一个恢复信号，即COOH末端四肽Lys-Asp-Glu-Leu（KDEL），1它与顺式高尔基体区域的膜受体结合并将其返回ER。事实上，KDEL受体能够从沿着分泌途径的远至TGN处回收逃逸的ER驻留蛋白;从细胞表面引入TGN的具有COOH末端KDEL序列的外源性合成肽随后被转运至ER腔（20）。最近，某些蛋白质毒素从表面到ER腔遵循相同的路线变得明显。为了到达哺乳动物细胞的胞质溶胶中的目标，毒素显然更进一步并穿过ER膜。支持这一点的新兴实验证据在这里进行审查。
The synthesis, segregation, intracellular transport, and exocytic export of secretory proteins in eukaryotic cells is now well understood. Synthesis begins on free cytosolic ribosomes that subsequently attach to the ER, resulting in the cotranslational discharge of the nascent proteins into the ER lumen. The targeting signals and the cytosolic and ER membrane components that mediate the translocation step have been extensively characterized and reviewed (for example, see 29). The ER lumen contains a range of resident proteins responsible for modifying newly synthesized polypeptides, and for ensuring correct folding into the biologically active conformation (9). Secretion entails transport of the proteins from the ER, via the Golgi stack and the TGN, to secretory vesicles that ultimately fuse with the plasma membrane to complete protein export. The secretory pathway was elucidated by Palade and his colleagues (24). Protein transport between the various compartments of the secretory pathway is mediated by carrier vesicles that bud from one compartment and fuse with the next. Once again, many of the cellular components that are required for, and that regulate, vesicular transport have been identified, and the mechanisms by which cytoplasmic protein coats drive the individual transport steps are now emerging (31). It has been recognized for some time that the secretory pathway is at least partially reversible. For example, retrograde vesicular transport from the Golgi to the ER is needed to retrieve resident ER proteins that have escaped from this compartment (25), and endocytosis can transport proteins from the cell surface to the TGN (2), which is the cellular location where the secretory and endocytic pathways converge (31). ER resident proteins contain a retrieval signal, the COOH-terminal tetrapeptide Lys-Asp-Glu-Leu (KDEL), 1 which binds to a membrane receptor in the cis-Golgi region and returns them to the ER. Indeed the KDEL receptor is capable of retrieving escaped ER resident proteins from as far along the secretory pathway as the TGN; an exogenous synthetic peptide with a COOH-terminal KDEL sequence, which was introduced into theTGN from the cell surface was subsequently transported to the ER lumen (20). Recently, it has become apparent that certain protein toxins follow this same route from the surface to the ER lumen. To reach their targets in the cytosol of mammalian cells the toxins apparently go one step further and cross the ER membrane. The emerging experimental evidence in support of this is reviewed here.