Extracellular proteostasis prevents aggregation during pathogenic attack

Ivan Gallotta, Aneet Sandhu, Maximilian Peters, Martin Haslbeck, Raimund Jung, Sinem Agilkaya, Jane L. Blersch, Christian Rödelsperger, Waltraud Röseler, Chaolie Huang, Ralf J. Sommer and Della C. David ()
Additional contact information
Ivan Gallotta: German Center for Neurodegenerative Diseases (DZNE)
Aneet Sandhu: German Center for Neurodegenerative Diseases (DZNE)
Maximilian Peters: Hebrew University of Jerusalem
Martin Haslbeck: Technical University of Munich
Raimund Jung: German Center for Neurodegenerative Diseases (DZNE)
Sinem Agilkaya: German Center for Neurodegenerative Diseases (DZNE)
Jane L. Blersch: German Center for Neurodegenerative Diseases (DZNE)
Christian Rödelsperger: Max Planck Institute for Developmental Biology, Department for Integrative Evolutionary Biology
Waltraud Röseler: Max Planck Institute for Developmental Biology, Department for Integrative Evolutionary Biology
Chaolie Huang: German Center for Neurodegenerative Diseases (DZNE)
Ralf J. Sommer: Max Planck Institute for Developmental Biology, Department for Integrative Evolutionary Biology
Della C. David: German Center for Neurodegenerative Diseases (DZNE)

Nature, 2020, vol. 584, issue 7821, 410-414

Abstract: 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 proteins1–5. 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 pathogens6–9, 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.

Date: 2020
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DOI: 10.1038/s41586-020-2461-z

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