Unravelling signalling pathways controlling proteasome homeostasis under stressful conditions

错误折叠和受损的蛋白质随着年龄的增长而积累，这种蛋白质组的逐渐崩溃被定义为衰老的标志之一，并导致各种人类疾病，如癌症和神经变性。通过清除这些缺陷蛋白的泛素-蛋白酶体系统（UPS）是维持蛋白质组完整性的重要组成部分。我们的工作重点是更好地理解控制蛋白酶体组装和活性的信号通路。这是一个非常基本和重要的问题，与理解健康老龄化和人类疾病有着密切的联系。我们最近表明，激酶Mpk1/ERK5在各种蛋白质毒性胁迫下控制蛋白酶体的稳态。因此，我们对鉴定蛋白酶体稳态调节所需的Mpk1/ERK5底物特别感兴趣。这项研究将提供关于磷酸化如何调节应激条件下蛋白酶体降解和生存的见解。由于癌细胞经常依赖于高水平的蛋白酶体，因此发现是否有任何关键的鉴定底物在癌症中发生突变也将是令人兴奋的。由于蛋白酶体的核心功能是清除错误折叠和不需要的蛋白质，这一建议也可能有助于开发新的策略来增加蛋白酶体的能力，这可能有利于治疗神经退行性疾病。

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.