Ubiquitin-specific-processing protease 14 (USP14) (USP14)

Ubiquitin-specific-processing protease 14 (USP14) is a major deubiquitinating enzyme (DUB) that reversibly associates with the 19S regulatory particle of the 26S proteasome [1, 8]. It plays a pivotal role in the ubiquitin-proteasome system by trimming ubiquitin chains from substrates, which can either facilitate their degradation or rescue them from being broken down [1, 4]. Beyond its role in proteostasis, USP14 is involved in diverse cellular processes, including autophagy, signal transduction pathways like NF-κB and Wnt/β-catenin, and innate immune responses [3, 10]. In many cancers, USP14 is overexpressed and correlates with poor prognosis by stabilizing oncogenic proteins and promoting cell proliferation [12, 13]. It is also implicated in neurodegenerative diseases, where it may regulate the clearance of misfolded protein aggregates [4, 5]. Therapeutic strategies focus on small-molecule inhibitors, such as IU1 and b-AP15, which aim to induce proteotoxic stress and apoptosis in malignant cells [11, 15]. However, achieving high selectivity among the large DUB family and managing potential toxicities, such as the lung toxicity observed in clinical trials of some inhibitors like VLX1570, remain significant challenges in drug development [3, 7].

Other names

Ubiquitin carboxyl-terminal hydrolase 14Deubiquitinating enzyme 14Ubiquitin thioesterase 14TGT

Inhibition of the deubiquitinating activity of USP14, leading to increased degradation of proteasome-bound substrates or accumulation of polyubiquitinated proteins, which induces proteotoxic stress and apoptosis.