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The ubiquitin-proteasome system (UPS) plays a central role in most cellular processes. Recent data suggest that the UPS plays a role beyond the well-known housekeeping function of protein turnover and highlight that more needs to be done to understand the complex nature of the UPS and its functions in the cell. We are studying the UPS starting from basic cellular functions and working to understand its involvement in human diseases ranging from muscle atrophies to cancer. In addition, our efforts are focused on developing new molecular, chemical and biophysical technologies to gain insights into complex cellular processes.

     One focus of our work with translational potential is the “hijacking" of the UPS for targeted protein degradation with small molecules that have the potential to develop new therapeutic strategies. With this approach, we hope to unravel the “untreatable" proteome and develop a better strategy to combat diseases where therapeutic options are limited by conventional drug discovery approaches. One such targeted degradation tactic involves bifunctional molecules that recruit UPS components to degrade a target protein – better known as PROTACs (PROteolysis-TArgeting Chimeras). Another is molecular glue degraders that similarly recruit neosubstrates to E3 ligases for degradation.

    While conventional small molecules must block the aberrant activity of a target protein, PROTACs and molecular glue degraders serve to completely eliminate the protein by directing it to the proteasome for degradation by the ubiquitin system. Since both eliminate the target protein by degradation, similar to functional genetic approaches (e.g. RNAi and CRISPR/Cas9), we can correlate molecular changes and predict cellular phenotypes much better – something that conventional therapeutics usually cannot fully recapitulate. Since conventional small molecules are always subject to off-target effects, PROTACs and molecular glue degraders can greatly improve the predictability of gene function studies by mimicking the effects observed in conventional genetic ablation studies.

Another goal is to develop biotechnologies to answer important scientific questions that require a cellular context, such as monitoring cellular protein-ligand interactions. This research is led by my colleague Nicholas Valerie (staff.ki.se/people/nicval). Dr. Altun is a group leader at the Science for Life Laboratory (SciLifeLab) in Stockholm, an important hub for Sweden’s national life science infrastructures ( [1]).


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Acknolegments:

The lab will be forever grateful to the HÃ¥llsten family for supporting us from the beginning and always believing in what we do.