Advanced Tools to Uncover the Assembly and Regulation of Proteasome Variants

• Funding – self-funded/externally sponsored applicants   (PhD Fees can be found here)
• Applications are accepted year round
• Standard Entry dates – January and September
• Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline.

Protein homeostasis and the regulation of protein degradation by the proteasome are fundamental cellular processes that maintain health by ensuring the proper synthesis, folding, and degradation of proteins. The failure of proteostasis is at the core of pathologies like neurodegeneration, a leading cause of disability, dependency, and death globally. Despite its critical importance, the molecular mechanisms that control protein homeostasis and proteasome function remain poorly understood. The Rousseau lab is interested in developing new technologies to explore the mechanistic control of proteasome variants in health and disease. 

The proteasome consists of a 20S core particle, which houses the proteolytic sites, and one or two regulatory particles (RPs) that recognise, unfold, and translocate substrates into the 20S for degradation. The primary RP, known as the 19S, mediates ubiquitin-dependent protein degradation and is commonly referred to as the conventional proteasome. Alternative RPs, such as PA28 and PA200, regulate ubiquitin-independent degradation and play key roles in immune response and nuclear integrity, respectively. Another layer of complexity is the existence of cell-type and context-dependent proteasome variants that diversify its functional repertoire, allowing adaptation to various cellular contexts. One of our main goals is to define the spatio-temporal regulation of proteasome assembly and activity in health, stress and diseases using both yeast and mammalian systems. This includes assembly and regulation of the poorly characterised alternative forms of the proteasome. 

The PhD project aims to (1) engineer the proteasome to develop innovative tools for monitoring the assembly of its alternative forms in living cells, (2) use these tools to uncover the mechanistic details of proteasome variant assembly, and (3) examine how stress and disease conditions impact proteasome variant assembly. The project offers training in cutting-edge technologies, including cell engineering (CRISPR-Cas9 editing of proteasome genes), molecular biology (proteasome and protein degradation assays), and high-resolution confocal microscopy (proteasome dynamics), applied to both yeast and mammalian systems.

Recent lab contributions: 

  Williams, T. D., Winaya, A., Joshua, I., & Rousseau, A (2023) Proteasome assembly chaperone translation upon stress requires Ede1 phase separation at the plasma membrane iScience 27 doi:10.1016/j.isci.2023.108732 PMID: 38235332 

  Black, A., Williams, T. D., Soubigou, F., Joshua, I. M., Zhou, H., Lamoliatte, F., & Rousseau, A (2023) The ribosome-associated chaperone Zuo1 controls translation upon TORC1 inhibition EMBO Journal 42 e113240 doi:10.15252/embj.2022113240 PMID: 37984430 

  Agrotis A, Lamoliatte F, Williams TD, Black A, Horberry R, Rousseau A (2023) Multiple phosphorylation of the Cdc48/p97 cofactor protein Shp1/p47 occurs upon cell stress in budding yeast Life Sciences Alliance 6 doi:10.26508/lsa.202201642 PMID: 36693698 

  Williams, T., Cacioppo, R., Agrotis, A., Black, A., Zhou, H., & Rousseau, A (2022) Actin remodelling controls proteasome homeostasis upon stress Nature Cell Biology  doi:10.1038/s41556-022-00938-4 PMID: 35739319

  Adrien Rousseau and Anne Bertolotti (2016) An evolutionarily conserved pathway controls proteasome homeostasis. Nature 536 184–189 PMID: 27462806 

  Ariane Hanssum, Zhen Zhong, Adrien Rousseau, Agnieszka Krzyzosiak, Anna Sigurdardottir and Anne Bertolotti (2014) An inducible chaperone adapts proteasome assembly to stress Mol. Cell  55 566–577 PMID: 25042801 

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.