Ubiquitin-specific protease 14 is a new therapeutic target for the treatment of diseases.

Ubiquitin-specific protease 14 (USP14) is a ubiquitin-specific protease that is associated with the proteasome and plays important roles in cellular functions, viral infection, inflammatory responses, neurodegenerative diseases, and tumorigenesis. USP14 appears to have a dual function in regulating intracellular proteolytic degradation. USP14 impedes degradation of ubiquitinated proteins by removing ubiquitin chains from its substrates, while it could promote protein degradation via increasing proteasome activation. Increasing evidence has shown that USP14 is also involved in the regulation of autophagy. Thus, USP14 might act as a key regulator in two major intracellular proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. The important roles of USP14 in multiple diseases have encouraged the development of clinically viable USP14 antagonists. This review summarizes the current state of knowledge about the regulation of USP14 expression, activity, and its functions in physiological and pathological processes.