The importance of protein homeostasis has come to permeate many aspects of modern biology. Aberrant protein species and undesirable protein aggregates, if not cleared properly, compromise protein homeostasis and ultimately culminate in devastating diseases, collectively called as proteopathies.
Especially, the 26S proteasome is the principal protease for specific degradation of harmful proteins – the process known as protein quality control. The ubiquitin-proteasome system (UPS) is indeed an important drug target for human health insofar as FDA-approved proteasome inhibitors are effective in the treatment of a growing list of cancers. Deubiquitinating enzymes (DUBs), numbering over a hundred in human proteome, exclusively reverse the ubiquitination, regulate ubiquitin pool, and antagonize protein destruction (e.g. including aberrant proteins and oncoprotein). DUBs are also emerging as promising drug targets, due to their involvement in human diseases. Furthermore, DUB inhibitors may serve as specific tools for discovering novel biology in the ubiquitin-proteasome pathways.
My research primarily focused on key regulatory mechanisms occurring on the proteasome. I discovered that USP14, a major proteasome-associated deubiquitinating enzyme, acts as a critical inhibitory component on the proteasome. In addition, recently I have established a high-throughput small-molecule chemical screening platform, and as a proof-of-principle, discovered drug-like molecules targeting USP14. Highly specific USP14 inhibitors are cell-permeable and can serve as a potent enhancer of proteasome function. Through medicinal chemistry, I also have developed more potent and selective variants of USP14 inhibitors. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce aberrant proteins for human health. By employing this inhibitor, I also discovered truly unanticipated supernumerary chain-specific and en bloc cleavage mechanisms governed by USP14, which occurring only on the proteasome. This is to our knowledge the first report of such a preference within the family of deubiquitinating enzymes.
This research defines proteasome and deubiquitinating enzymes in the ubiquitin-proteasome system as promising drug targets for human health. This study also highlights the significance of cellular proteome balance in normal and diseased states, and will eventually enhance our general understanding of protein homeostasis for human health.
-Ubiquitin-proteasome pathway, deubiquitination reaction on the proteasome, and a specific USP14 inhibitor IU1
Protein homeostasis through the ubiquitin-proteasome system (UPS) is critical in almost every aspect of basic and clinical biology. Our lab is particularly interested in understanding cellular protein quality control system and developing the strategies for improving proteostasis by manipulating the UPS. We will primarily investigate critical deubiquitination machinery in human pathophysiology. Our group will try to develop functional and chemical strategies to modulate the deubiquitination activities on the proteasome and at the upstream of proteasome to explore novel biological mechanisms in the ubiquitin-proteasome pathways. By developing new DUB inhibitors, we aim to define novel drug targets in protein quality control machinery and ultimately seek for potential therapeutic strategies for human health.
1. Discovery of novel deconjugation mechanisms in the ubiquitin-proteasome pathways for cell physiology
2. Investigation of novel regulatory mechanisms in ubiquitin deconjugation activities for proteasome function
3. Defining deubiquitinating enzymes as novel drug targets in oncogenesis and other human diseases by functional and chemical studies
4. Defining proteasome and deubiquitinating enzymes as novel drug targets in human longevity by combinatorial approaches of chemical and functional studies
-Understanding deubiquitination reactions on the proteasome as novel drug targets for cellular homeostasis