The Rousseau lab is dedicated to decoding how proteasome-mediated protein degradation is regulated in cells to prevent the harmful accumulation of unfolded, misfolded, or damaged proteins. The proteasome recognises, unfolds, and degrades proteins tagged with ubiquitin, thereby safeguarding proteome integrity. By degrading 80–90% of intracellular proteins, the proteasome is a central hub of the protein homeostasis network, preventing the toxic buildup of protein aggregates that can impair cellular function.

Defects in proteasome function are directly linked to a range of human diseases, including cancer and neurodegenerative disorders. We recently reported that proteasome assembly and activity increase in response to stress, enabling cells to remodel their proteome and enhance survival (Rousseau lab). Our current work focuses on the spatiotemporal regulation of proteasome assembly and activity under conditions of health, stress, and disease, in both yeast and mammalian systems. A particular emphasis is placed on the assembly and function of poorly characterised alternative proteasome variants.

The PhD project aims to engineer the proteasome and develop new technologies to monitor the assembly of its alternative forms, in a format suitable for high-throughput screening. These tools will be instrumental in uncovering the functions of alternative proteasome complexes and in clarifying their involvement in disease. For example, mutations in proteasome subunits cause proteasomopathies (juvenile neurodevelopmental disorders), while mutations in proteasome-associated proteins are linked to early-onset Parkinson’s disease. Ultimately, this work will lay the foundation for novel strategies to restore protein homeostasis in neurodegenerative disorders. The project will offer training opportunities in state-of-the-art technologies such as cell engineering (CRISPR-Cas9 gene editing of proteasome genes), molecular biology (proteasome and protein degradation assays), and high-resolution confocal microscopy (proteasome dynamics).

References

1: Adrien Rousseau and Anne Bertolotti. Regulation of proteasome assembly and activity in health and disease. Nat Rev Mol Cell Biol (2018), 19, 697–712

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

3: Thomas Williams, Roberta Cacioppo, Alexander Agrotis, Ailsa Black, Houjiang Zhou and Adrien Rousseau. Actin remodelling controls proteasome homeostasis upon stress. Nat Cell Biol 24, 1077–1087 (2022).

4: Ailsa Black, Thomas Williams, Houjiang Zhou and Adrien Rousseau. The ribosome-associated chaperone Zuo1 controls translation upon TORC1 inhibition. EMBO Journal, (2023).

5: Thomas David Williams, Aurellia Ramara and Adrien Rousseau. Proteasome Assembly Chaperone Translation Upon Stress Requires Ede1 Phase Separation at the Plasma Membrane. iScience, (2023).