Structure and function of the highly homologous deubiquitinases ubiquitin specific peptidase 25 and 28: Insights into their pathophysiological and therapeutic roles.

Deubiquitination is the reverse process of ubiquitination, an important protein post-translational modification. Deubiquitination is assisted by deubiquitinating enzymes (DUBs), which catalyze the hydrolysis and removal of ubiquitin chains from targeted proteins and play an important role in regulating protein stability, cell signaling transduction, and programmed cell death. Ubiquitin-specific peptidases 25 and 28 (USP25 and USP28), important members of the USP subfamily of DUBs, are highly homologous, strictly regulated, and closely associated with various diseases, such as cancer and neurodegenerative diseases. Recently, the development of inhibitors targeting USP25 and USP28 for disease treatment has garnered extreme attention. Several non-selective and selective inhibitors have shown potential inhibitory effects. However, the specificity, potency, and action mechanism of these inhibitors remain to be further improved and clarified. Herein, we summarize the structure, regulation, emerging physiological roles, and target inhibition of USP25 and USP28 to provide a basis for the development of highly potent and specific inhibitors for the treatment of diseases, such as colorectal cancer, breast cancer and so on.

Ubiquitin-specific protease 20 in human disease: Emerging role and therapeutic implications.

Ubiquitination is one of the most important post-translational protein modifications; the linking of the 76-amino-acid polypeptide ubiquitin dictates protein fate. Deubiquitinating enzymes (DUBs) can specifically remove ubiquitin attached to substrate proteins, thereby stabilizing the protein and preventing its degradation through the proteasome. The balance between ubiquitination and deubiquitination plays a key role in maintaining protein function and in regulating cellular homeostasis. The development of drugs targeting DUBs has attracted the widespread attention of scientists and pharmaceutical companies. Ubiquitin-specific protease 20 (USP20) belongs to the ubiquitin-specific peptidase (USP) subfamily of DUBs and its important physiological role has been assessed in recent years. Previous studies on USP20 have focused on its activity in antiviral immunity and cancer. However, its role in metabolic disorders and neurological diseases has also been revealed. The physiological importance of USP20 in disease is being reported continuously, indicating its potential to be a valuable therapeutic target in the future. The small molecule inhibitor GSK2643943A has been shown to inhibit the deubiquitination activity of USP20. Herein, we discuss the structure, regulation, and emerging physiological roles of USP20 in disease, hoping to highlight their therapeutic implications for future studies.

USP13: Multiple Functions and Target Inhibition.

As a deubiquitination (DUB) enzyme, ubiquitin-specific protease 13 (USP13) is involved in a myriad of cellular processes, such as mitochondrial energy metabolism, autophagy, DNA damage response, and endoplasmic reticulum-associated degradation (ERAD), by regulating the deubiquitination of diverse key substrate proteins. Thus, dysregulation of USP13 can give rise to the occurrence and development of plenty of diseases, in particular malignant tumors. Given its implications in the stabilization of disease-related proteins and oncology targets, considerable efforts have been committed to the discovery of inhibitors targeting USP13. Here, we summarize an overview of the recent advances of the structure, function of USP13, and its relations to diseases, as well as discovery and development of inhibitors, aiming to provide the theoretical basis for investigation of the molecular mechanism of USP13 action and further development of more potent druggable inhibitors.