Through regulating Ubiquitin E3 ligase in achieving degradation of aggregated protein and suppression of cell death in polyglutamine degeneration

Abstract

Polyglutamine (polyQ) diseases, including Huntington’s disease and several types of spinocerebellar ataxias, are caused by the genomic expansion of coding CAG trinucleotide sequences. This expansion leads to the production and accumulation of misfolded polyQ domain‐containing disease proteins, which cause cellular dysfunction and neuronal death. As one of the principal cellular protein clearance pathways, the activity of the ubiquitin proteasome system (UPS) is tightly regulated to ensure efficient clearance of damaged and toxic proteins. Emerging evidence demonstrates that the UPS plays a crucial role in the pathogenesis of polyQ diseases. Ubiquitin (Ub) E3 ligases catalyze the transfer of a Ub tag to label proteins destined for proteasomal clearance. We recently identified an E3 ligase Y that modulates expanded polyQ‐induced neurodegeneration in both mammalian and Drosophila disease models. We further showed that Y promotes poly‐ubiquitination and degradation of expanded polyQ protein. Our data further demonstrated the nuclear localization of Y is essential for it to function as a polyQ E3 ligase. Intriguingly, we found that an exocyst complex component X, a Y interacting partner, modulates expanded polyQ protein levels and toxicity in an opposite manner to Y. Our data suggest that X exerts, at least in part, its polyQ‐modifying effect through regulating the E3 ligase function of Y. In summary, this study allows us to better define the role of protein ubiquitination in polyQ pathogenesis and understand how the E3 ligase activity can be regulated in a pathogenic condition.Support or Funding InformationThis work was supported by General Research Fund (14122815) of The Research Grants Council of Hong Kong and CUHK Gerald Choa Neuroscience Centre Grant (7105306).