Rewiring of the ubiquitinated proteome determines ageing in C. elegans

Seda Koyuncu, Rute Loureiro, Hyun Ju Lee, Prerana Wagle, Marcus Krueger and David Vilchez ()
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Seda Koyuncu: University of Cologne
Rute Loureiro: University of Cologne
Hyun Ju Lee: University of Cologne
Prerana Wagle: University of Cologne
Marcus Krueger: University of Cologne
David Vilchez: University of Cologne

Nature, 2021, vol. 596, issue 7871, 285-290

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03781-z

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