Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates.
Prions on the run: How extracellular vesicles serve as delivery vehicles for self-templating protein aggregates.
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DOI：
10.1080/19336896.2017.1306162
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发表时间：
2017-03-04
期刊：
影响因子：
2.3
通讯作者：
Vorberg IM
中科院分区：
文献类型：
--
作者：
Liu S;Hossinger A;Göbbels S;Vorberg IM
细胞外囊泡（EV）是主动分泌的、膜结合的通信媒介，其在细胞之间交换生物分子。EV还充当病原体的传播媒介，包括朊病毒、在哺乳动物中引起传染性海绵状脑病（TSE）的蛋白质感染剂。越来越多的证据表明，与常见神经退行性疾病相关的各种蛋白质聚集体也被包装到EV中。囊泡介导的蛋白质聚集体的细胞间传递可以诱导受体细胞中同型蛋白质的聚集，从而可能有助于疾病的进展。我们对蛋白质聚集体如何被分选成EV以及这些囊泡如何粘附并与靶细胞融合的知识是有限的。在这里，我们回顾TSE朊病毒如何利用EV的细胞间传输，并比较这一传输行为的自模板胞质蛋白聚集体来自酵母朊病毒结构域Sup 35 NM。人工NM朊病毒对哺乳动物细胞培养物是无毒的，并且不引起功能丧失表型。重要的是，NM颗粒也与外泌体结合分泌，外泌体将朊病毒表型水平传递给幼稚旁观者细胞，这是一个可以通过自动化高通量共聚焦显微镜高精度监测的过程。高丰度的哺乳动物蛋白质的氨基酸组成上类似于酵母朊病毒结构域的延伸，使NM细胞模型的一个有吸引力的模型，研究自模板和传播特性的蛋白质与朊病毒样结构域在哺乳动物的情况下。
Extracellular vesicles (EVs) are actively secreted, membrane-bound communication vehicles that exchange biomolecules between cells. EVs also serve as dissemination vehicles for pathogens, including prions, proteinaceous infectious agents that cause transmissible spongiform encephalopathies (TSEs) in mammals. Increasing evidence accumulates that diverse protein aggregates associated with common neurodegenerative diseases are packaged into EVs as well. Vesicle-mediated intercellular transmission of protein aggregates can induce aggregation of homotypic proteins in acceptor cells and might thereby contribute to disease progression. Our knowledge of how protein aggregates are sorted into EVs and how these vesicles adhere to and fuse with target cells is limited. Here we review how TSE prions exploit EVs for intercellular transmission and compare this to the transmission behavior of self-templating cytosolic protein aggregates derived from the yeast prion domain Sup 35 NM. Artificial NM prions are non-toxic to mammalian cell cultures and do not cause loss-of-function phenotypes. Importantly, NM particles are also secreted in association with exosomes that horizontally transmit the prion phenotype to naive bystander cells, a process that can be monitored with high accuracy by automated high throughput confocal microscopy. The high abundance of mammalian proteins with amino acid stretches compositionally similar to yeast prion domains makes the NM cell model an attractive model to study self-templating and dissemination properties of proteins with prion-like domains in the mammalian context.