AbstractUbiquitination and deubiquitination are the important types of post-translational modifications that are involved in the regulation of most complex cellular processes. USP17, a member of the ubiquitin specific protease (USP) family of deubiquitinases, has been shown to be required for cell cycle progression, cell motility, endocytosis and our previous studies have preliminarily shown it is required for lysosome positioning. The research presented in this thesis further confirm the role of USP17 in lysosome trafficking and explore the impact upon lysosomal function as well as its potential mechanism.
The data presented in Chapter 3 of this thesis shows the impact of USP17 upon lysosomal trafficking and lysosome-related processes. USP17 depletion affects lysosome peripheral trafficking and the degradation of extracellular matrix. Additionally, USP17 is essential for EGF triggered lysosome periphery trafficking and proper plasma membrane repair (PMR). The results in this chapter also suggest that USP17 may impact upon autophagy and TFEB nuclear translocation, however more research is still required to confirm these impacts of USP17.
The data presented in Chapter 4 studies the potential mechanisms by which USP17 regulates the lysosome. Firstly, RCE1 iso2, a previously identified substrate of USP17, is shown not to be involved in lysosome trafficking. YIPF proteins are found to be regulated by USP17 and YIPF1, as well as YIPF2, may be implicated in lysosome trafficking. However, a clear mechanism via which USP17 directly regulates YIPF proteins is lacking. Moreover, the impact of USP17 upon Sec31A could indicate an impact upon ER-to-Golgi transport, but again, a clear mechanism is not apparent. Finally, USP17 is shown to be involved in the RNF26-based network which can regulate lysosome positioning via the ubiquitination of p62 to tether vesicles to the ER, and in particular USP17 is shown to deubiquitinate p62.
Overall, the data illustrates that USP17 is important for lysosome trafficking and lysosomal function. These findings provide us with more understanding about the function of USP17 as well as providing additional insight into the impact of any inhibitors that target USP17 for future drug research and development.
|Date of Award
|James Burrows (Supervisor) & Christopher Scott (Supervisor)
- lysosome trafficking
- lysosomal function