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Extracellular proteostasis prevents aggregation during pathogenic attack

机译：细胞外蛋白质是致病性攻击过程中的聚集

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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 proteins(1-5). 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 pathogens(6-9), 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.
机译：在甲氧唑烷中，分泌的蛋白质组参与细胞间信号传导和先天免疫，并在细胞周围构建细胞外基质支架。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是骚扰，并且低浓度的ATP可防止蛋白质质量控​​制机械的细胞内部件的活性。到目前为止，只有少数真正的细胞外伴侣和蛋白酶被证明限制细胞外蛋白的聚集（1-5）。在这里，我们对Caenorhabditis的细胞外蛋白杆菌网络进行了系统分析，RNA干扰筛选靶向编码分泌蛋白质组的基因。我们发现了57个细胞外蛋白质聚集的调节因子，包括几种与先天免疫有关的蛋白质。由于响应于病原体（6-9），细胞内蛋白质是上调的，因此我们研究了病原体是否刺激细胞外蛋白质。使用孔形成毒素来模拟致病性攻击，我们发现C.杆状杆菌通过增加细胞外蛋白质组分的表达以及通过限制细胞外蛋白的聚集而作出反应。细胞外蛋白质的激活依赖于应激活化的MAP激酶信号传导。值得注意的是，细胞外蛋白质延迟衰老和使蠕虫造成耐食性的过表达。我们提出增强的细胞外蛋白质通过维持功能性分泌的蛋白质组和避免蛋白毒性而导致全身宿主防御。

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  • 来源
    《Nature》 |2020年第7821期|410-414|共5页
  • 作者

    Gallotta Ivan; Sandhu Aneet; Peters Maximilian; Haslbeck Martin; Jung Raimund; Agilkaya Sinem; Blersch Jane L.; Roedelsperger Christian; Roeseler Waltraud; Huang Chaolie; Sommer Ralf J.; David Della C.;

  • 作者单位

    German Ctr Neurodegenerat Dis DZNE Tubingen Germany;

    German Ctr Neurodegenerat Dis DZNE Tubingen Germany|Univ Tubingen Grad Training Ctr Neurosci Int Max Planck Res Sch Tubingen Germany;

    Hebrew Univ Jerusalem Dept Med Neurobiol Jerusalem Israel;

    Tech Univ Munich Dept Chem Garching Germany;

    German Ctr Neurodegenerat Dis DZNE Tubingen Germany;

    German Ctr Neurodegenerat Dis DZNE Tubingen Germany;

    German Ctr Neurodegenerat Dis DZNE Tubingen Germany|Univ Tubingen Grad Training Ctr Neurosci Int Max Planck Res Sch Tubingen Germany;

    Max Planck Inst Dev Biol Dept Integrat Evolutionary Biol Tubingen Germany;

    Max Planck Inst Dev Biol Dept Integrat Evolutionary Biol Tubingen Germany;

    German Ctr Neurodegenerat Dis DZNE Tubingen Germany;

    Max Planck Inst Dev Biol Dept Integrat Evolutionary Biol Tubingen Germany;

    German Ctr Neurodegenerat Dis DZNE Tubingen Germany|Univ Tubingen Interfac Inst Biochem Tubingen Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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