Elucidating the redox-proteolysis switch for transcriptional induction of the ubiquitin proteasome system (UPS) in space and time (A13)

蛋白毒性应激伴随着活性氧(ROS)的产生和内质网应激的诱导。转录反馈环通过激活内质网连接的转录因子TCF11来调节UPS依赖的蛋白质降解，以响应蛋白毒性和氧化应激。TCF11的膜释放和核转位是由ROS和膜旁蛋白水解酶切割组成的分子开关触发的。该项目旨在利用先进的细胞生物学、细胞培养和线虫中的化学和遗传工具，阐明这种控制细胞反应的开关，以时空分辨率重新平衡氧化还原和蛋白质动态平衡。

Proteotoxic stress is accompanied by the production of reactive oxygen species (ROS) and by induction of ER stress. A transcriptional feed-back-loop regulates UPS-dependent protein degradation in response to proteotoxic and oxidative stress via activation of the ER-tethered transcription factor TCF11. The membrane release and nuclear translocation of TCF11 is triggered by a molecular switch comprising ROS and a juxta-membrane proteolytic cleavage. The project aims to elucidate this switch controlling cellular responses to rebalance redox and protein homeostasis with spatial and temporal resolution using advanced cell biology, chemical and genetic tools in cell culture and C. elegans.