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Ubiquitin-dependent signalling pathways in ageing


School of Biological Sciences

About the Project

Ageing is characterized by a general functional decline of cells with increased risk of disease. Maintenance of protein homeostasis is a long-term challenge not only for individual cells but also for the entire organism. In recent years it became evident that ubiquitin-dependent regulation of signalling pathways regulate numerous cellular processes and have a major impact on organismal aging. The age-related impairment of ubiquitin-dependent proteolysis results in enhanced accumulation of damaged proteins and organelles which can lead to loss of cell integrity, tissue degeneration and can also shorten lifespan. On the other hand, direct ubiquitination of distinct lifespan regulators also actively influences the life expectancy of different organisms (1-4). Deubiquitinating enzymes (DUBs) are responsible for reversing the ubiquitination of proteins by removing ubiquitin moieties attached to the substrates. DUBs are emerging as critical regulators of the stability, activity, complex formation and intracellular localization of a wide variety of proteins. Consequently, DUBs play key regulatory roles in a multitude of processes, and their dysfunction is linked to various human diseases. Despite intensive research there is only little known about the potential function of DUBs maintenance of the aging proteome. This project will focus on defining the tissue specific role of DUBs in healthy aging. This research will benefit from the use of the model organism Caenorhabditis elegans and the well-established molecular, genetic, biochemistry and cell biology methods available in this system. The major aim is to understand how failure of ubiquitin-dependent regulation leads to cellular and tissue dysfunction and affects aging of the whole organism.

Funding Notes

Applicants should hold or expect to gain a minimum of a 2:1 Bachelor Degree or equivalent in a Biology related subject. Experience with C. elegans or with cell culture would be advantageous, but not a pre-requisite.

References

1. Kevei, E. & Hoppe, T. (2014) Ubiquitin sets the timer: impacts on aging and longevity, Nature structural & molecular biology. 21, 290-2.
2. Kevei, E., Pokrzywa, W. & Hoppe, T. (2017) Repair or destruction-an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis, FEBS letters. 591, 2616-2635.
3. Tawo, R., Pokrzywa, W., Kevei, E., Akyuz, M. E., Balaji, V., Adrian, S., Hohfeld, J. & Hoppe, T. (2017) The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover, Cell. 169, 470-482 e13.
4. Kuhlbrodt, K., Janiesch, P. C., Kevei, E., Segref, A., Barikbin, R. & Hoppe, T. (2011) The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis, Nat Cell Biol. 13, 273-81.


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