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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.
Lim JJ, Noh S, Kang W, Hyun B, Lee BH#, Hyun S#. Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner. Autophagy. 2024 Dec;20(12):2752-2768. doi: 10.1080/15548627.2024.2389607. Epub 2024 Aug 15. (# Corresponding Author)
Hung KY, Klumpe S, Eisele M, Elsasser S, Tian G, Sun S, Moroco J, Cheng T, Joshi T, Seibel T, van Dalen D, Feng XH, Lu Y, Ovaa H, Engen J, Lee BH#, Rudack T#, Sakata E#, and Finley D# (2022) Allosteric control of Ubp6 and the proteasome via a bidirectional switch. Nat. Commun. 13(1):838. doi: 10.1038/s41467-022-28186-y (# Co-corresponding 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).
Lee BH, Min X, Heise CJ, Xu BE, Chen S, Shu H, Luby-Phelps K, Goldsmith EJ, and Cobb MH. (2004) WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding. Mol. Cell 15, 741-751.