Ubiquitin-carrying enzymes (green) in human cells. Image credit: Hill et al. (CC BY 4.0)
Proteins are the molecules that perform most of the tasks that keep cells alive, but often they need to be removed. If human cells lose control over protein degradation it can result in diseases such as cancer or neurodegenerative disorders.
The enzymes responsible for tagging proteins for destruction are called ubiquitin ligases. Drugs that hijack ubiquitin ligases to tag disease-causing proteins have been successfully used to treat a cancer called multiple myeloma. Encouragingly, human cells have over 600 ubiquitin ligases and most have not yet been tested as therapeutic targets. A clear understanding of how these enzymes work in human cells could therefore lead to new therapies for conditions such as cancer.
To tag a protein for degradation, ubiquitin ligases transfer a small protein (ubiquitin) from a ubiquitin-carrying enzyme to the target protein. In yeast, this process is relatively simple, since in many cases there is a one-to-one relationship between each ubiquitin ligase and its ubiquitin-carrying enzyme partner. In human cells, on the other hand, the process seems to be more complex. The biggest family of ubiquitin ligases in humans is the cullin-RING ligase family, and the number of partner ubiquitin-carrying enzymes for this family remains unknown, as are the effects of different interactions between members of the family and different ubiquitin-carrying enzymes.
Now, Hill et al. have used biochemical assays to measure the activities of four ubiquitin-carrying enzymes that partner with cullin-RING ligases. They found that while certain proteins can be tagged for degradation by different combinations of the cullin-RING ligases and the ubiquitin-carrying enzymes, others display preferences for specific ubiquitin-modifying enzymes partnering up. The experiments also revealed that one of the ubiquitin-carrying enzymes tested was active at high concentrations, but could not tag proteins when assayed at concentrations closer to those found in the cell. Finally, Hill et al. genetically removed two of the ubiquitin-carrying enzymes and showed that, unlike in yeast, a third ubiquitin-carrying enzyme could compensate for their loss, a redundancy that makes the system robust.
These results show that the human cullin-RING ligases can interact with multiple ubiquitin-carrying enzyme partners. Controlled protein degradation affects every major activity in human cells, and a good understanding of the mechanisms that regulate this process can help researchers better understand many biological processes. Additionally, these findings are relevant to the development of therapies trying to use ubiquitin ligases to remove faulty proteins.
