Rewiring of the ubiquitinated proteome determines ageing in C. elegans

Seda Koyuncu, Rute Loureiro, Hyun Ju Lee, Prerana Wagle, Marcus Krueger, David Vilchez

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Ageing is driven by a loss of cellular integrity1. Given the major role of ubiquitin modifications in cell function2, 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 proteasome3, 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 filament4 and the EPS-8 modulator of RAC signalling5. 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.

Original languageEnglish
Pages (from-to)285-290
Number of pages6
JournalNature
Volume596
Issue number7871
DOIs
StatePublished - 12 Aug 2021
Externally publishedYes

Fingerprint

Dive into the research topics of 'Rewiring of the ubiquitinated proteome determines ageing in C. elegans'. Together they form a unique fingerprint.

Cite this