Universität zu Köln

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

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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
Creators:	Creators Email ORCID ORCID Put Code Koyuncu, Seda UNSPECIFIED UNSPECIFIED UNSPECIFIED Loureiro, Rute UNSPECIFIED orcid.org/0000-0002-2023-2429 UNSPECIFIED Lee, Hyun Ju UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagle, Prerana UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Vilchez, David UNSPECIFIED orcid.org/0000-0002-0801-0743 UNSPECIFIED
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
Uncontrolled Keywords:	Keywords Language CAENORHABDITIS-ELEGANS; STEM-CELLS; LIFE-SPAN; PROTEINS; RNAI; MAINTENANCE; AGGREGATION; INTEGRITY; REVEALS; SYSTEM Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/56914