2) Regulation of Parkin by Deubiquitination

A striking feature of parkin and other E3 Ub-ligases is their ability to ubiquitinate themselves. Typically, this leads to targeting of the E3 to the proteasome for degradation. However, this self-ubiquitination is reversible, as many E3s interact with specific deubiquitinating enzymes (DUBs), which catalyze the removal of Ub conjugates from the E3. As a result, one or more DUB can stabilize an E3 by removing the Ub conjugates that are targeting it for degradation. Indeed, our previous work demonstrated that parkin can be deubiquitinated and identified ataxin-3 as the first DUB partner for parkin (Durcan et al. 2011 Hum. Mol. Genet.; Durcan et al. 2012 J. Biol. Chem.). However, E3s are often regulated promiscuously by multiple DUBs. Given the diversity of processes in which parkin plays a role, we speculate that in addition to ataxin-3, other DUBs also regulate its function via deubiquitination. In a project funded by the Parkinson Society Canada, we have taken an unbiased approached to screen for additional DUB partners of parkin and identified several candidates. Given the potential role of deubiquitination in regulating parkin function and the inherent “druggability” of DUBs, this project has the potential to uncover promising new targets for PD therapeutics.