Koyuncu, Seda, Loureiro, Rute ORCID: 0000-0002-2023-2429, Lee, Hyun Ju, Wagle, Prerana, Krueger, Marcus and Vilchez, David
ORCID: 0000-0002-0801-0743
(2021).
Rewiring of the ubiquitinated proteome determines ageing in C. elegans.
Nature, 596 (7871).
S. 285 - 317.
BERLIN:
NATURE PORTFOLIO.
ISSN 1476-4687
Abstract
Ageing is driven by a loss of cellular integrity(1). Given the major role of ubiquitin modifications in cell function(2), here we assess the link between ubiquitination and ageing by quantifying whole-proteome ubiquitin signatures in Caenorhabditis elegans. We find a remodelling of the ubiquitinated proteome during ageing, which is ameliorated by longevity paradigms such as dietary restriction and reduced insulin signalling. Notably, ageing causes a global loss of ubiquitination that is triggered by increased deubiquitinase activity. Because ubiquitination can tag proteins for recognition by the proteasome(3), a fundamental question is whether deficits in targeted degradation influence longevity. By integrating data from worms with a defective proteasome, we identify proteasomal targets that accumulate with age owing to decreased ubiquitination and subsequent degradation. Lowering the levels of age-dysregulated proteasome targets prolongs longevity, whereas preventing their degradation shortens lifespan. Among the proteasomal targets, we find the IFB-2 intermediate filament(4) and the EPS-8 modulator of RAC signalling(5). While increased levels of IFB-2 promote the loss of intestinal integrity and bacterial colonization, upregulation of EPS-8 hyperactivates RAC in muscle and neurons, and leads to alterations in the actin cytoskeleton and protein kinase JNK. In summary, age-related changes in targeted degradation of structural and regulatory proteins across tissues determine longevity.
Item Type: | Journal Article | ||||||||||||||||||||||||||||
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URN: | urn:nbn:de:hbz:38-569147 | ||||||||||||||||||||||||||||
DOI: | 10.1038/s41586-021-03781-z | ||||||||||||||||||||||||||||
Journal or Publication Title: | Nature | ||||||||||||||||||||||||||||
Volume: | 596 | ||||||||||||||||||||||||||||
Number: | 7871 | ||||||||||||||||||||||||||||
Page Range: | S. 285 - 317 | ||||||||||||||||||||||||||||
Date: | 2021 | ||||||||||||||||||||||||||||
Publisher: | NATURE PORTFOLIO | ||||||||||||||||||||||||||||
Place of Publication: | BERLIN | ||||||||||||||||||||||||||||
ISSN: | 1476-4687 | ||||||||||||||||||||||||||||
Language: | English | ||||||||||||||||||||||||||||
Faculty: | Unspecified | ||||||||||||||||||||||||||||
Divisions: | Unspecified | ||||||||||||||||||||||||||||
Subjects: | no entry | ||||||||||||||||||||||||||||
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URI: | http://kups.ub.uni-koeln.de/id/eprint/56914 |
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