Ubiquitin-specific protease 14 and Ubiquitin carboxyl-terminal hydrolase L5 (USP14/UCHL5)

Ubiquitin-specific protease 14 (USP14) and Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5, also known as UCH37) are two of the three primary deubiquitinating enzymes (DUBs) associated with the 19S regulatory particle of the 26S proteasome [1.2.2, 1.4.2]. These enzymes are responsible for removing ubiquitin chains from protein substrates before they are translocated into the 20S proteolytic core for degradation [1.1.1, 1.3.2]. By recycling ubiquitin and regulating the rate of substrate entry, USP14 and UCHL5 play a vital role in maintaining cellular protein homeostasis [1.4.2, 1.5.4]. In various malignancies, including multiple myeloma and Waldenström macroglobulinemia, these DUBs are frequently overexpressed, allowing cancer cells to survive high levels of proteotoxic stress [1.2.2, 1.3.1]. Small molecule inhibitors such as b-AP15 and its clinical-stage analog VLX1570 have been developed to target both USP14 and UCHL5 simultaneously [1.1.1, 1.1.2]. Inhibition of these DUBs leads to a rapid accumulation of poly-ubiquitinated proteins, triggering the unfolded protein response (UPR) and inducing apoptosis, even in cells resistant to traditional 20S proteasome inhibitors like bortezomib [1.1.2, 1.2.3]. Despite their potent anti-tumor activity in preclinical models, the clinical development of dual USP14/UCHL5 inhibitors has been hampered by safety concerns, most notably the severe pulmonary toxicity observed in Phase 1 trials of VLX1570 [1.1.1, 1.2.4].

Other names

USP14UCHL5UCH37Ubiquitin-specific-processing protease 14Ubiquitin carboxyl-terminal hydrolase 37CGI-92TGTdeubiquitinating enzyme 14

Dual inhibition of USP14 and UCHL5 deubiquitinating activity at the 19S proteasome, leading to accumulation of poly-ubiquitinated proteins, proteotoxic stress, and induction of the unfolded protein response (UPR) and apoptosis.