Dysregulation of proteolysis and proteostasis accumulates aberrant and intractable protein species in cells and often cause devastating human diseases. The central focus of our group is to understand critical proteolytic machinery, such as proteasome and deubiquitinating enzymes (DUBs), in human health and define them as promising drug targets. A hallmark of our research highlights the significance of cellular proteome balance in normal and diseased states. We will strive to pioneer the protein degradation mechanisms from both biology and therapeutic perspectives, and eventually provide new and foundational paradigms in the field.

Current interests in the lab can be summarized into a few of subjects:

•Screening and profiling deubiquitinating enzymes (DUBs) that are critically involved in human diseases

•Development of high-throughput chemical screening of DUB inhibitors for proteolytically targeting the disease-associated proteins

•Elucidating and deciphering dynamic nature of DUB reactions for proteolytic versatility

Another area of our interest is how to develop novel chemical strategies to dispose of the challenging or  “undruggables” targets by induced protein degradation.

Our group is particularly interested in developing the strategies for improving proteostasis by manipulating the ubiquitin-proteasome system (UPS). Notably, DUBs may represent promising drug targets in impaired proteostasis, due to their capability of regulating protein half-lives. Therefore, DUBs that are associated with human diseases will be also identified from chemo-genomic screening approaches and then will be evaluated for their potential to regulate the stability of disease-related proteins and undruggable targets.

Proteasome serves as a critical hub as well as a rate limiting step for the proteolytic degradation pathway, and whose activity can be under dynamic regulation by proteasome-associated factors, such as DUBs. Thus, we will try to investigate dynamic nature of DUB reactions on the proteasome and upstream of the proteasome for offering fundamental basis of proteolytic versatility.

Three distinct classes of DUBs—USP14, RPN11, and UCH37—are associated with the human proteasome. These enzymes exert dynamic influence over proteasome output with limited redundancy, and at times act in opposition. Such distinct activities occur spatially on the proteasome, temporally through substrate processing, and differentially for ubiquitin topology. Our lab will try to study how DUBs on the proteasome can fine-tune the degradation for dynamic proteolysis outcomes.

Given that DUBs are critical checkpoints in the proteolytic pathway and proteasome is the rate limiting step for substrate engagement in protein degradation, we try to develop novel class of chemical proteolytic inducers for directly engaging DUBs or proteasome into the undruggable targets. These DUB- or proteasome-guided degradation inducers may significantly innovate the conventional paradigm of targeted protein degradation because they might bypass the obligatory requirement of polyubiquitin chains as the typical degradation signal.