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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.
Pubmed ID: 34321666
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View all literature mentionsA quantitative proteomics software package for analyzing large-scale mass-spectrometric data sets. It is a set of algorithms that include peak detection and scoring of peptides, mass calibration, database searches for protein identification, protein quantification, and provides summary statistics.
View all literature mentionsSoftware that supports biological and biomedical researchers in interpreting protein quantification, interaction and post-translational modification data. Perseus contains a comprehensive portfolio of statistical tools for high-dimensional omics data analysis covering normalization, pattern recognition, time-series analysis, cross-omics comparisons and multiplehypothesis testing.
View all literature mentionsCaenorhabditis elegans with name eat-2(ad1116) II. from WB.
View all literature mentionsCaenorhabditis elegans with name daf-16(mgDf50) I; daf-2(e1370) III from WB.
View all literature mentionsThis monoclonal targets alpha-Tubulin
View all literature mentionsThis monoclonal targets EGFP, GFP, YFP
View all literature mentionsThis polyclonal targets Phospho-SAPK/JNK (Thr183/Tyr185)
View all literature mentionsThis monoclonal targets Ubiquitin, Lys63-Specific
View all literature mentionsThis monoclonal targets Ubiquitin
View all literature mentionsThis monoclonal targets intermediate filament subunit
View all literature mentionsThis polyclonal targets FLAG
View all literature mentionsThis polyclonal targets SAPK/JNK
View all literature mentionsThis monoclonal targets Ubiquitin, Lys48-Specific
View all literature mentionsThis monoclonal targets beta Actin
View all literature mentionsThis polyclonal targets EPS8L2 antibody
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