Rewiring of the ubiquitinated proteome determines ageing in C. elegans

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.

Protein clearance strategies for disease intervention

“…Thus, the activities of E3 ligases and DUBs are tightly balanced to maintain intracellular proteostasis and cellular function (Bax et al 2019 ; Choi and Baek 2018 ). In these lines, the landscape of E3 and DUB enzymes undergo a profound rewiring during transformative processes such as cell differentiation or organismal aging (Koyuncu et al 2021 ; Saez et al 2018 ).

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“…In C. elegans , there is an increase in global DUB activity during the aging process. Consequently, multiple proteins escape the clean-up by the UPS and accumulate with age, leading to protein aggregation and cellular dysfunction (Koyuncu et al 2021 ). Moreover, deregulation of DUBs is involved in many different neurological disorders such as AD, PD, HD, and ALS (Amer-Sarsour et al 2021 ; Nazé et al 2002 ; Saigoh et al 1999 ; Setsuie and Wada, 2007 ; Zeng et al 2019 ).…”

Pollutants corrupt resilience pathways of aging in the nematode C. elegans

“…The copyright holder for this this version posted September 29, 2021. ; https://doi.org/10.1101/2021.09.28.461818 doi: bioRxiv preprint sequestration of its components to protein aggregates with age causes an increasing solubility imbalance in the organism highlighted by the insolubility of structural proteins in the agedinduced aggregome. In agreement, IFB-2 was identified as one of 10 age-dysregulated proteasomal targets, which mislocalizes into cytosolic protein aggregates linked to loss of intestinal integrity (Koyuncu et al, 2021). Further, knockdown of ifb-2 in adult C. elegans results in an increased lifespan and better intestinal health (Koyuncu et al, 2021).…”

“…In agreement, IFB-2 was identified as one of 10 age-dysregulated proteasomal targets, which mislocalizes into cytosolic protein aggregates linked to loss of intestinal integrity (Koyuncu et al, 2021). Further, knockdown of ifb-2 in adult C. elegans results in an increased lifespan and better intestinal health (Koyuncu et al, 2021). Future studies that include longitudinal experiments could time stamp the appearance of different functional protein groups in the insoluble fraction and allow construction of an insolubility time line.…”

Flavonoids—Natural Gifts to Promote Health and Longevity

“…The quality of the protein is guaranteed by the translation mechanism and the activity of auxiliary proteins (including molecular chaperones), while degradation is controlled by autophagy and proteasome functions. The accumulation of protein damage in the aging process is mainly due to (i) decreased translation fidelity [20,21], (ii) downregulation of protein chaperones [22,23], and (iii) decreased proteasome activity [24] and other factors in protein synthesis and quality control. Damaged proteins contribute to proteostatic stress, the accumulation of misfolded/aggregated proteins, and protein toxicity, which further aggravate the senescence of cells.…”