Wyatt Amy R, Yerbury Justin J, Dabbs Rebecca A, Wilson Mark R
School of Biological Sciences, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
J Mol Biol. 2012 Aug 24;421(4-5):499-516. doi: 10.1016/j.jmb.2012.01.004. Epub 2012 Jan 10.
Extracellular protein misfolding and aggregation underlie many of the most serious amyloidoses including Alzheimer's disease, spongiform encephalopathies and type II diabetes. Despite this, protein homeostasis (proteostasis) research has largely focussed on characterising systems that function to monitor protein conformation and concentration within cells. We are now starting to identify elements of corresponding systems, including an expanding family of secreted chaperones, which exist in the extracellular space. Like their intracellular counterparts, extracellular chaperones are likely to play a central role in systems that maintain proteostasis; however, the precise details of how they participate are only just emerging. It is proposed that extracellular chaperones patrol biological fluids for misfolded proteins and facilitate their clearance via endocytic receptors. Importantly, many amyloidoses are associated with dysfunction in rates of protein clearance. This is consistent with a model in which disruption to, or overwhelming of, the systems responsible for extracellular proteostasis results in the accumulation of pathological protein aggregates and disease. Further characterisation of mechanisms that maintain extracellular proteostasis will shed light on why many serious diseases occur and provide us with much needed strategies to combat them.
细胞外蛋白质错误折叠和聚集是许多最严重的淀粉样变性疾病的基础，包括阿尔茨海默病、海绵状脑病和II型糖尿病。尽管如此，蛋白质稳态（蛋白质平衡）研究主要集中在表征细胞内监测蛋白质构象和浓度的系统。我们现在开始识别相应系统的组成部分，包括细胞外空间中存在的一个不断扩大的分泌型伴侣蛋白家族。与它们在细胞内的对应物一样，细胞外伴侣蛋白可能在维持蛋白质平衡的系统中发挥核心作用；然而，它们如何参与其中的精确细节才刚刚开始显现。有人提出，细胞外伴侣蛋白在生物体液中巡查错误折叠的蛋白质，并通过内吞受体促进其清除。重要的是，许多淀粉样变性疾病与蛋白质清除率的功能障碍有关。这与一种模型一致，即负责细胞外蛋白质稳态的系统受到破坏或不堪重负会导致病理性蛋白质聚集体的积累和疾病。对维持细胞外蛋白质稳态机制的进一步表征将阐明许多严重疾病发生的原因，并为我们提供对抗这些疾病急需的策略。
