Periodic Reporting for period 1 - StressRhomboid (Trapping intramembrane protease substrates in living cells: focus on RHBDL4 role in ERAD)
Période du rapport: 2020-07-29 au 2022-07-28
As a ubiquitously expressed protein, RHBDL4 is likely crucial for fundamental cellular processes. Unveiling its role can unlock valuable insights into basic cellular functions and potentially uncover therapeutic targets for combating various diseases.
The first objective was to develop a protease substrate discovery assay that utilized a newly discovered substrate trapping mechanism. This innovative approach involved genetic replacement of the active site serine with an unnatural amino acid. The second objective aimed to investigate the role of RHBDL4 in the ER stress. ER stress is a cellular state associated with numerous diseases, including neurodegenerative disorders and diabetes. The third objective was to find components of ERAD associated RHBDL4 complex.
In collaboration with LMB Cambridge, the project established a protease trapping assay. This breakthrough technique enabled the discovery of novel and surprising substrates, the majority of which were found to be soluble.
The project's findings, published in the prestigious journal Nature, led to a shift in the direction of inquiry. Instead of solely focusing on RHBDL4's role in ER stress, we redirected their attention to the identified substrates. This strategic shift holds promise for uncovering new avenues of research and deepening our understanding of cellular processes influenced by RHBDL4.