ER and Post-ER Quality Control of Integral Membrane Proteins

真核生物中大约三分之一新合成的蛋白质进入内质 网状结构（ER）。一旦与该区室结合，这些新生的多肽就被后 翻译处理，获取其本机确认，寡聚，并分类 细胞外分泌或输送到其他细胞器。然而，许多疾病 突变会损害蛋白质折叠和成熟，进而产生聚集 易发品种。抵消蛋白质积累带来的灾难性影响 聚集体，错误折叠的蛋白质底物是：（i）由相关的分子伴侣选择 与 ER 一起，(ii) 用泛素修饰，(iii) 通过称为 逆转录转位，以及 (iv) 被 26S 蛋白酶体降解。布罗茨基和同事命名 该途径与 ER 相关降解 (ERAD) 相关，在过去 21 年中，许多 布罗德斯基实验室定义了这一系列事件背后的分子机制。至 迄今为止，约 80 种人类疾病与 ERAD 通路相关，并且已发表超过 1,200 篇出版物 撰写了该途径的各个方面的文章。持续的努力正在定义 几种 ERAD 相关疾病的病理生理学基础。与此同时，成员 Brodsky 实验室揭示了关键组件如何协调 ERAD 期间的每个步骤。在 过去5年，该实验室发表了64篇论文，并开发了工具和技术 对导致选择、泛素化、 逆转位和不同底物的降解。尽管如此，最近的发现 决定了要追求更具挑战性的研究方向：必然地，这些下一步的努力 将需要额外的方法开发和对长期目标的追求。具体 该研究计划将解决的问题包括： 哪些生化特征定义了 ERAD底物？哪些因素足以驱动 ERAD 底物的逆转位， 其中一些容易聚集？ ER 相关蛋白酶是否与 ER 相关蛋白酶协同作用？ 26S 蛋白酶体破坏稳定整合到 ER 膜中的底物，以及 因此可能具有逆转录抗性吗？而且，逆转位膜蛋白是如何—— 从内质网中释放出来后，它可以驻留在细胞质中——保留在可溶状态吗？ 这些问题的答案是该领域研究的核心，将显着 增进对面对蛋白毒性应激时如何维持细胞健康的理解 以及 ERAD 相关疾病如何产生以及如何纠正。

Approximately one-third of all newly synthesized proteins in eukaryotes enter the endoplasmic reticulum (ER). Once associated with this compartment, these nascent polypeptides are post- translationally processed, acquire their native confirmations, oligomerize, and are sorted for extracellular secretion or delivery to other organelles. However, many disease-causing mutations compromise protein folding and maturation, which in turn can generate aggregation- prone species. To off-set the catastrophic effects that accompany the accumulation of protein aggregates, misfolded protein substrates are: (i) selected by molecular chaperones associated with the ER, (ii) modified with ubiquitin, (iii) delivered to the cytoplasm via a process known as retrotranslocation, and (iv) degraded by the 26S proteasome. Brodsky and colleagues named this pathway ER associated degradation (ERAD), and over the past 21 years many of the molecular mechanisms underlying this sequence of events were defined in the Brodsky lab. To date, ~80 human diseases are linked to the ERAD pathway and >1,200 publications have been authored on various aspects of this pathway. Ongoing efforts are defining the pathophysiological foundation of several ERAD-related disorders. In parallel, members of the Brodsky lab have revealed how key components orchestrate each step during ERAD. In the past 5 years, the lab has published 64 papers, and tools and technologies were developed that provide an unprecedented view of the mechanisms that lead to the selection, ubiquitination, retrotranslocation, and degradation of diverse substrates. Nevertheless, recent discoveries dictate that more challenging research directions are pursued: By necessity, these next efforts will require additional method development and a pursuit of longer-term goals. Specific questions that the research program will address include: What biochemical features define an ERAD substrate? Which factors are sufficient to drive the retrotranslocation of ERAD substrates, some of which are aggregation-prone? Do ER-associated proteases function in tandem with the 26S proteasome to destroy substrates that are stably integrated into the ER membrane, and thus might be retrotranslocation resistant? And, how are retrotranslocated membrane proteins— which can reside in the cytosol after being liberated from the ER—retained in a soluble state? Answers to these questions, which lie at the core of research in the field, will significantly advance an understanding of how cellular health is maintained in the face of proteotoxic stress as well as how ERAD-associated diseases arise and might be rectified.