Ubiquitin-specific peptidase (USP)

Ubiquitin-specific peptidases (USPs) represent the largest and most diverse subfamily of deubiquitinating enzymes (DUBs), comprising over 50 members in humans that catalyze the removal of ubiquitin from target proteins [1][2]. These enzymes are critical regulators of the ubiquitin-proteasome system, effectively rescuing proteins from degradation or modulating non-proteolytic signaling pathways by cleaving isopeptide bonds between ubiquitin and the substrate [2][3]. USPs are frequently dysregulated in various pathologies; for instance, USP7 is often exploited by cancer cells to destabilize the tumor suppressor p53, while USP14 is involved in regulating proteasomal activity in neurodegenerative contexts [4]. From a drug discovery perspective, USPs are highly druggable cysteine proteases, and small-molecule inhibitors are being actively developed to treat oncology, inflammatory, and neurodegenerative indications [4][5]. However, achieving selectivity remains a significant challenge due to the structural conservation of the catalytic domain across the USP family [5]. [1] Komander, D., et al. (2009). Nature Reviews Molecular Cell Biology. [2] Nijman, S. M., et al. (2005). Cell. [3] Mevissen, T. E., & Komander, D. (2017). Annual Review of Biochemistry. [4] Harrigan, J. A., et al. (2018). Nature Reviews Drug Discovery. [5] Pozhidaeva, A., & Bezsonova, I. (2019). International Journal of Molecular Sciences.

Other names

Ubiquitin-specific proteaseUbiquitin carboxyl-terminal hydrolaseDeubiquitinating enzymeDUB

Inhibition of the catalytic cysteine residue within the USP domain to prevent the cleavage of ubiquitin from substrate proteins, thereby promoting their proteasomal degradation or altering their functional signaling.