Cellular Functions of Proteasome-Associated Ubiquitin Ligase Activity

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The ubiquitin-26S proteasome has vital roles in cellular signalling by selectively degrading proteins that are short-lived or damaged. In eukaryotes attachment of the conserved small protein ubiquitin marks substrates for recruitment to the proteasome where they are proteolysed into small peptides. Failure to degrade ubiquitin-marked substrates causes severe cellular stress and is a leading cause of developmental defects across different eukaryotes, including human pathologies such as neurodegenerative diseases, autoimmunity, cardiomyopathy, and genetic disorders like cystic fibrosis. Understanding the conserved regulatory mechanisms that govern healthy proteasome functioning therefore has the potential to impact diverse fields in biomedicine and biotechnology. Recent findings indicate that upon arrival at the proteasome, substrates may undergo further modification by ubiquitin. But why do substrates require further polyubiquitination if they have already been recruited to the proteasome? Although it has been suggested that such 'last-minute' polyubiquitination facilitates proteasome processivity, the mechanisms underpinning this activity remain elusive. We recently demonstrated that ubiquitin ligases from the HECT-type family physically associate with the proteasome, thereby governing universal substrate polyubiquitination and associated phenotypical traits. Intriguingly, HECT-type ligases interact with multiple E3 ubiquitin ligases from distinct signalling pathways. Based on these findings we propose to elucidate the substrate repertoires of HECT-type ligases and explore new hypotheses for their role in signalling: (1) does healthy proteasome function require substrate relay from multiple E3 ligases to proteasome-associated HECT-type ligases?; (2) do proteasome-associated HECT-type ligases modify the activity of interacting E3 ligases, thereby enabling proteasomes to feedback regulate ubiquitin-mediated signalling pathways? Understanding how HECT-type ligases promote proteasome function will aid in targeted design of new strategies to improve proteasome function during disease.