TY  - JOUR
AU  - Gallotta, Ivan
AU  - Sandhu, Aneet
AU  - Peters, Maximilian
AU  - Haslbeck, Martin
AU  - Jung, Raimund
AU  - Agilkaya, Sinem
AU  - Blersch, Jane L.
AU  - Rödelsperger, Christian
AU  - Röseler, Waltraud
AU  - Huang, Chaolie
AU  - Sommer, Ralf J.
AU  - David, Della
TI  - Extracellular proteostasis prevents aggregation during pathogenic attack
JO  - Nature  / Physical science
VL  - 584
IS  - 7821
SN  - 1476-4687
CY  - London
PB  - Macmillan28177
M1  - DZNE-2020-01427
SP  - 410 - 414
PY  - 2020
AB  - 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.
KW  - Aging: metabolism
KW  - Animals
KW  - Caenorhabditis elegans: cytology
KW  - Caenorhabditis elegans: genetics
KW  - Caenorhabditis elegans: metabolism
KW  - Caenorhabditis elegans: microbiology
KW  - Caenorhabditis elegans Proteins: metabolism
KW  - Extracellular Space: metabolism
KW  - Fatty Acid-Binding Proteins: metabolism
KW  - MAP Kinase Signaling System
KW  - Protein Aggregates
KW  - Protein Aggregation, Pathological: prevention & control
KW  - Proteome: genetics
KW  - Proteome: metabolism
KW  - Proteostasis
KW  - RNA Interference
LB  - PUB:(DE-HGF)16
C6  - pmid:32641833
DO  - DOI:10.1038/s41586-020-2461-z
UR  - https://pub.dzne.de/record/153430
ER  -