Ubiquitin specific peptidase 6 (USP6)

Ubiquitin specific peptidase 6 (USP6) is a primate-specific deubiquitinating enzyme involved in the removal of ubiquitin moieties from target proteins, opposing the action of ubiquitin ligases and thereby regulating protein stability, localization, and function[1][3][5]. Structurally, USP6 consists of a USP (ubiquitin-specific protease) domain and an atypical TBC/Rab-GAP domain, but the TBC domain lacks typical GTPase-activating protein function and instead interacts with Arf6, influencing plasma membrane trafficking[3]. USP6 plays a significant role in regulating cellular pathways including NFκB and Wnt signaling, protein homeostasis, cell cycle progression, and neural synapse function[2][3][5]. Pathologically, USP6 is notable for its recurrent gene rearrangements found in benign and malignant bone and soft tissue tumors (e.g., aneurysmal bone cyst, nodular fasciitis, Ewing sarcoma) and is increasingly recognized as an oncogene. Additionally, USP6 has been implicated in synaptic plasticity and neurodevelopment, with links to disorders such as intellectual disability and autism spectrum disorder[2]. As a therapeutic target, inhibition of USP6 deubiquitinase activity (e.g., using PR-619) is being explored for its potential anti-tumor applications[3]. USP6's highly restricted expression in adult tissues, absence in most animal models, and complex roles in cancer, immunity, and neurobiology make it a unique and challenging target for drug development[1][3][5].

Other names

Ubiquitin carboxyl-terminal hydrolase 6TRE17Tre-2HRP1RN-treUbiquitin thioesterase 6Proto-oncogene TRE-2Ubiquitin-specific-processing protease 6USP6(short)Deubiquitinating enzyme 6TBC1D3 and USP32 fusionTre-2 oncogeneTRESMCRhyperpolymorphic gene 1

Inhibition of USP6 with PR-619 blocks deubiquitinase activity, leading to accumulation of polyubiquitinated proteins, cell cycle arrest, and induction of apoptosis in malignant cells