Unravelling signalling pathways controlling proteasome homeostasis under stressful conditions

Misfolded and damaged proteins accumulate with age and this progressive collapse of the proteome is defined as one of the hallmarks of ageing and contributes to various human diseases such as cancer and neurodegeneration. The Ubiquitin-Proteasome system (UPS) by clearing these faulty proteins is an essential component to maintain the integrity of the proteome. Our work focuses on better understanding signalling pathways that control proteasome assembly and activity. This is a very fundamental and important question with strong links to understanding healthy aging and human disease. We have recently shown that the kinase Mpk1/ERK5 controls proteasome homeostasis upon various proteotoxic stresses. Thus, we are particularly interested in identifying Mpk1/ERK5 substrates which are required for the regulation of proteasome homeostasis. This study will provide insights on how phosphorylation regulates proteasomal degradation and survival upon stressful conditions. As cancer cells are often addicted to high levels of proteasomes, it will also be exciting to uncover whether any of the key identified substrates are mutated in cancers. With the central function of the proteasome in clearing misfolded and unwanted proteins, this proposal might also help developing new strategies to increase proteasome capacity with the idea that this could be beneficial to treat neurodegenerative diseases.