Ubiquitin Specific Peptidase 14 (USP14) is a member of the ubiquitin-specific processing (UBP) family of proteases. It is a deubiquitinating enzyme (DUB) that plays a crucial role in the ubiquitin-proteasome system, which is essential for protein degradation and regulation within the cell . USP14 is encoded by the USP14 gene and is located in the cytoplasm, where it cleaves the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins .
USP14 is associated with proteasomes and exerts a dual function in regulating protein degradation. It protects protein substrates from degradation by removing ubiquitin chains from proteasome-bound substrates, while also promoting protein degradation by activating the proteasome . The activity of USP14 is tightly regulated to ensure its function in various cellular processes, including cancer, neurodegenerative diseases, autophagy, immune responses, and viral infections .
USP14 has been implicated in several canonical signaling pathways, correlating with various diseases. For instance, it is involved in the degradation of the chemokine receptor CXCR4, which is critical for CXCL12-induced cell chemotaxis . Additionally, USP14 is associated with diseases such as diabetic retinopathy and microvascular complications of diabetes .
The activity of USP14 is regulated through its association with the proteasome and phosphorylation. Structural studies have shown that free USP14 exists in an autoinhibited state with two surface loops, BL1 and BL2, partially blocking the active site cleft. Both proteasome-bound and phosphorylated forms of USP14 require conformational changes in the BL2 loop to activate its deubiquitinating function .
Due to its roles in stabilizing disease-causing proteins and oncology targets, USP14 has garnered interest as a therapeutic target. Significant progress has been made in identifying inhibitors targeting USP14, despite the challenges in improving their selectivity and affinity. The crystal structures of USP14 complexed with IU1-series inhibitors have revealed the underlying allosteric regulatory mechanism, enabling the design of potent inhibitors .