德国图宾根大学Della C. David小组发现，细胞外蛋白稳态可防止病原体攻击时的蛋白聚集。该研究于2020年7月8日在线发表于《自然》。

通过RNA干扰筛选编码分泌蛋白的基因，研究人员对秀丽隐杆线虫的细胞外蛋白稳态网络进行了系统分析。研究人员发现了57种细胞外蛋白聚集调节因子，包括几种与先天免疫有关的蛋白。由于细胞内蛋白稳态响应病原体而上调，研究人员调查了病原体是否也刺激细胞外蛋白稳态。使用打孔毒素来模拟病原性攻击，研究人员发现秀丽隐杆线虫通过增加细胞外蛋白稳定成分的表达以及限制细胞外蛋白质的聚集来作出反应。细胞外蛋白稳态的活化取决于应激活化的MAP激酶信号。

值得注意的是，细胞外蛋白稳态成分的过度表达延缓了衰老，并使线虫对醉酒具有抵抗力。研究人员认为，细胞外蛋白稳态的增强通过维持功能性分泌蛋白组以及避免蛋白毒性来帮助系统性宿主防御。

据了解，在后生动物中，分泌的蛋白质组参与细胞间信号传导和先天免疫，并在细胞周围建立细胞外基质支架。与相对恒定的细胞内环境相比，细胞外空间中蛋白质的条件更为苛刻，并且低浓度的ATP阻止了蛋白质控机器胞内组分的活性。迄今为止，仅发现少量真正的细胞外伴侣和蛋白酶能够限制细胞外蛋白的聚集。

附：英文原文

Title: Extracellular proteostasis prevents aggregation during pathogenic attack

Author: Ivan Gallotta, Aneet Sandhu, Maximilian Peters, Martin Haslbeck, Raimund Jung, Sinem Agilkaya, Jane L. Blersch, Christian Rdelsperger, Waltraud Rseler, Chaolie Huang, Ralf J. Sommer, Della C. David

Issue&Volume: 2020-07-08

Abstract: In metazoans, the secreted proteome participates in intercellular signalling and innate immunity, and builds the extracellular matrix scaffold around cells. Compared with the relatively constant intracellular environment, conditions for proteins in the extracellular space are harsher, and low concentrations of ATP prevent the activity of intracellular components of the protein quality-control machinery. Until now, only a few bona fide extracellular chaperones and proteases have been shown to limit the aggregation of extracellular proteins1,2,3,4,5. Here we performed a systematic analysis of the extracellular proteostasis network in Caenorhabditis elegans with an RNA interference screen that targets genes that encode the secreted proteome. We discovered 57 regulators of extracellular protein aggregation, including several proteins related to innate immunity. Because intracellular proteostasis is upregulated in response to pathogens6,7,8,9, we investigated whether pathogens also stimulate extracellular proteostasis. Using a pore-forming toxin to mimic a pathogenic attack, we found that C. elegans responded by increasing the expression of components of extracellular proteostasis and by limiting aggregation of extracellular proteins. The activation of extracellular proteostasis was dependent on stress-activated MAP kinase signalling. Notably, the overexpression of components of extracellular proteostasis delayed ageing and rendered worms resistant to intoxication. We propose that enhanced extracellular proteostasis contributes to systemic host defence by maintaining a functional secreted proteome and avoiding proteotoxicity.

DOI: 10.1038/s41586-020-2461-z

Source: https://www.nature.com/articles/s41586-020-2461-z