Protein homeostasis (aka, proteostasis) – the equilibrium and optimal biological function of cellular proteins – is crucial for proper cellular functioning; its
imbalance is closely associated with diverse human diseases, including neurodegeneration and cancers.
Maintenance of proteostasis is attained through the coordinated action of the proteolytic machinery that preserve the proteome integrity.
Especially, the critical contribution of ubiquitin-proteasome system(UPS) to cellular proteostasis has been increasingly recognized in recent years.
We strive to understand cellular proteolytic mechanisms and develop new strategies for improving proteostasis by exploiting the UPS.
We are particularly interested in investigating proteasome, the master player in protein degradation,
and critical deubiquitinating enzymes (DUBs) in human pathophysiology.
Our group is trying to develop chemo-genomic methods to modulate the deubiquitinatio n activities acting upstream of and on the proteasome to explore novel deubiquitination biology. By developing new class of chemical proteolytic inducers and DUB inhibitors, we aim to define novel drug targets in protein quality control machinery and ultimately seek for proteolysis-based therapeutic strategies for human health.
Shin JY, Muniyappan S, Tran NN, Park H, Lee SB, and Lee BH (2020) Deubiquitination Reactions on the Proteasome for Proteasome Versatility. Int. J. Mol. Sci. Jul 27;21(15):E5312. doi: 10.3390/ijms21155312.
Moon S and Lee BH (2018) Chemically induced cellular proteolysis: an emerging therapeutic strategy for undruggable targets. Mol. Cells 41(11):933-942.
Boselli M*, Lee BH*, Robert J, Prado MA, Min SW, Cheng C, Silva MC, Seong C, Elsasser S, Hatle KM, Gahman TC, Gygi SP, Haggerty SJ, Gan L, King RW, and Finley D (2017) An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces elimination of phosphorylated tau in cultured neurons. J. Biol. Chem. 292(47):19209-19225 (* Co-first authors).
Lee BH#, Lu Y, Prado MA, Shi Y, Sun S, Elsasser S, Gygi SP, King RW#, and Finley D# (2016) USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites. Nature 532(7599):398-401 (# Co-corresponding authors).
Lu Y, Lee BH, King RW, Finley D, and Kirschner M (2015) Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science 348(6231):1250834.
Lee BH, Finley D, and King RW (2012) A High-Throughput Screening Method for Identification of Inhibitors of the Deubiquitinating Enzyme USP14. Curr. Protoc. Chem. Biol. 4:311-330, John Wiley & Sons, Inc.
Lee BH*, Lee MJ*, Park S, Oh DC, Elsasser S, Chen PC, Gartner C, Dimova N, Hanna J, Gygi SP, Wilson SM, King RW, and Finley D (2010) Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467:179-184 (* Co-first authors).