Robinson Claire M, Duggan Aislinn, Forrester Alison
School of Medicine, Health Sciences Centre, University College Dublin, Dublin, Ireland.
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Front Mol Biosci. 2024 Jan 18;11:1352970. doi: 10.3389/fmolb.2024.1352970. eCollection 2024.
The biosynthetic secretory pathway is comprised of multiple steps, modifications and interactions that form a highly precise pathway of protein trafficking and secretion, that is essential for eukaryotic life. The general outline of this pathway is understood, however the specific mechanisms are still unclear. In the last 15 years there have been vast advancements in technology that enable us to advance our understanding of this complex and subtle pathway. Therefore, based on the strong foundation of work performed over the last 40 years, we can now build another level of understanding, using the new technologies available. The biosynthetic secretory pathway is a high precision process, that involves a number of tightly regulated steps: Protein folding and quality control, cargo selection for Endoplasmic Reticulum (ER) exit, Golgi trafficking, sorting and secretion. When deregulated it causes severe diseases that here we categorise into three main groups of aberrant secretion: decreased, excess and altered secretion. Each of these categories disrupts organ homeostasis differently, effecting extracellular matrix composition, changing signalling events, or damaging the secretory cells due to aberrant intracellular accumulation of secretory proteins. Diseases of aberrant secretion are very common, but despite this, there are few effective therapies. Here we describe ER exit sites (ERES) as key hubs for regulation of the secretory pathway, protein quality control and an integratory hub for signalling within the cell. This review also describes the challenges that will be faced in developing effective therapies, due to the specificity required of potential drug candidates and the crucial need to respect the fine equilibrium of the pathway. The development of novel tools is moving forward, and we can also use these tools to build our understanding of the acute regulation of ERES and protein trafficking. Here we review ERES regulation in context as a therapeutic strategy.
生物合成分泌途径由多个步骤、修饰和相互作用组成，形成了一条高度精确的蛋白质运输和分泌途径，这对真核生物的生命至关重要。虽然该途径的大致轮廓已为人所知，但具体机制仍不清楚。在过去15年里，技术取得了巨大进步，使我们能够进一步了解这条复杂而微妙的途径。因此，基于过去40年所做工作的坚实基础，我们现在可以利用现有的新技术建立更深层次的理解。生物合成分泌途径是一个高精度的过程，涉及许多严格调控的步骤：蛋白质折叠和质量控制、内质网（ER）出芽的货物选择、高尔基体运输、分选和分泌。当调控失调时，会导致严重疾病，在此我们将其分为三类主要的异常分泌：分泌减少、分泌过多和分泌改变。这些类别中的每一种对器官内环境稳定的破坏方式都不同，影响细胞外基质组成、改变信号事件，或由于分泌蛋白在细胞内异常积累而损害分泌细胞。异常分泌疾病非常常见，但尽管如此，有效的治疗方法却很少。在这里，我们将内质网出芽位点（ERES）描述为分泌途径调控、蛋白质质量控制的关键枢纽以及细胞内信号整合的枢纽。本综述还描述了在开发有效治疗方法时将面临的挑战，这是由于潜在药物候选物需要具有特异性，并且至关重要的是要尊重该途径的精细平衡。新型工具的开发正在推进，我们还可以利用这些工具来加深对ERES和蛋白质运输急性调控的理解。在这里，我们将ERES调控作为一种治疗策略进行综述。
