Protein quality control through the ubiquitin-proteasome system is critical in almost every aspect of basic and clinical biology. Aberrant protein species and undesirable protein aggregates, if not cleared properly, compromise protein homeostasis and ultimately culminate in devastating diseases, which are collectively called as ‘proteopathies’. Especially, the 26S proteasome is increasingly recognized as a versatile player for fine-tuning the substrate degradation for maintaining protein homeostasis. Also, deubiquitinating enzymes, numbering over a hundred in human proteome, exclusively reverse the ubiquitination, and thereby potentially regulate protein turnover. We recently developed potent small-molecule inhibitors selectively targeting USP14, a major deubiquitinating enzyme on the proteasome. USP14 inhibitors can remarkably enhance the proteasome activity for potential therapeutic use, and also serve as specific tools to discover new deubiquitination biology on the proteasome. Our group primarily investigate critical deubiquitination machinery that are implicated in human pathophysiology. We plan to develop functional and chemical strategies to modulate deubiquitination reactions and thereby define them as novel regulators in maintaining protein homeostasis. This research will provide the fundamental basis for understanding cellular proteomic balance in normal and various disease states, and will also establish new druggable targets for human health.

Chemical approach to manipulate the protein degradation machinery for human health

255th National Meeting (2018)

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