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000153430 0247_ $$2ISSN$$a1476-4687
000153430 0247_ $$2ISSN$$a2058-1106
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000153430 1001_ $$0P:(DE-2719)2811903$$aGallotta, Ivan$$b0$$eFirst author
000153430 245__ $$aExtracellular proteostasis prevents aggregation during pathogenic attack
000153430 260__ $$aLondon$$bMacmillan28177$$c2020
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000153430 520__ $$aIn metazoans, the secreted proteome participates in intercellular signalling and innate immunity, and builds the extracellular matrix scaffold around cells. Compared with the relatively constant intracellular environment, conditions for proteins in the extracellular space are harsher, and low concentrations of ATP prevent the activity of intracellular components of the protein quality-control machinery. Until now, only a few bona fide extracellular chaperones and proteases have been shown to limit the aggregation of extracellular proteins1,2,3,4,5. Here we performed a systematic analysis of the extracellular proteostasis network in Caenorhabditis elegans with an RNA interference screen that targets genes that encode the secreted proteome. We discovered 57 regulators of extracellular protein aggregation, including several proteins related to innate immunity. Because intracellular proteostasis is upregulated in response to pathogens6,7,8,9, we investigated whether pathogens also stimulate extracellular proteostasis. Using a pore-forming toxin to mimic a pathogenic attack, we found that C. elegans responded by increasing the expression of components of extracellular proteostasis and by limiting aggregation of extracellular proteins. The activation of extracellular proteostasis was dependent on stress-activated MAP kinase signalling. Notably, the overexpression of components of extracellular proteostasis delayed ageing and rendered worms resistant to intoxication. We propose that enhanced extracellular proteostasis contributes to systemic host defence by maintaining a functional secreted proteome and avoiding proteotoxicity.
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000153430 650_2 $$2MeSH$$aAging: metabolism
000153430 650_2 $$2MeSH$$aAnimals
000153430 650_2 $$2MeSH$$aCaenorhabditis elegans: cytology
000153430 650_2 $$2MeSH$$aCaenorhabditis elegans: genetics
000153430 650_2 $$2MeSH$$aCaenorhabditis elegans: metabolism
000153430 650_2 $$2MeSH$$aCaenorhabditis elegans: microbiology
000153430 650_2 $$2MeSH$$aCaenorhabditis elegans Proteins: metabolism
000153430 650_2 $$2MeSH$$aExtracellular Space: metabolism
000153430 650_2 $$2MeSH$$aFatty Acid-Binding Proteins: metabolism
000153430 650_2 $$2MeSH$$aMAP Kinase Signaling System
000153430 650_2 $$2MeSH$$aProtein Aggregates
000153430 650_2 $$2MeSH$$aProtein Aggregation, Pathological: prevention & control
000153430 650_2 $$2MeSH$$aProteome: genetics
000153430 650_2 $$2MeSH$$aProteome: metabolism
000153430 650_2 $$2MeSH$$aProteostasis
000153430 650_2 $$2MeSH$$aRNA Interference
000153430 7001_ $$0P:(DE-2719)9001449$$aSandhu, Aneet$$b1$$udzne
000153430 7001_ $$aPeters, Maximilian$$b2
000153430 7001_ $$aHaslbeck, Martin$$b3
000153430 7001_ $$0P:(DE-2719)2811479$$aJung, Raimund$$b4
000153430 7001_ $$0P:(DE-2719)2812674$$aAgilkaya, Sinem$$b5
000153430 7001_ $$0P:(DE-2719)9001450$$aBlersch, Jane L.$$b6$$udzne
000153430 7001_ $$00000-0002-7905-9675$$aRödelsperger, Christian$$b7
000153430 7001_ $$aRöseler, Waltraud$$b8
000153430 7001_ $$0P:(DE-2719)2811852$$aHuang, Chaolie$$b9
000153430 7001_ $$00000-0003-1503-7749$$aSommer, Ralf J.$$b10
000153430 7001_ $$0P:(DE-2719)2810353$$aDavid, Della$$b11$$eLast author
000153430 773__ $$0PERI:(DE-600)2590711-6$$a10.1038/s41586-020-2461-z$$gVol. 584, no. 7821, p. 410 - 414$$n7821$$p410 - 414$$tNature <London> / Physical science$$v584$$x1476-4687$$y2020
000153430 8564_ $$uhttps://www.nature.com/articles/s41586-020-2461-z
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