Ubiquitin specific peptidase 3: an emerging deubiquitinase that regulates physiology and diseases

Abstract

Proteins are the keystone for the execution of various life activities, and the maintenance of protein normalization is crucial for organisms. Ubiquitination, as a post-transcriptional modification, is widely present in organisms, and it relies on the sophisticated ubiquitin-proteasome (UPS) system that controls protein quality and modulates protein lifespan. Deubiquitinases (DUBs) counteract ubiquitination and are essential for the maintenance of homeostasis. Ubiquitin specific peptidase 3 (USP3) is a member of the DUBs that has received increasing attention in recent years. USP3 is a novel chromatin modifier that tightly regulates the DNA damage response (DDR) and maintains genome integrity. Meanwhile, USP3 acts as a key regulator of inflammatory vesicles and sustains the normal operation of the innate immune system. In addition, USP3 is aberrantly expressed in a wide range of cancers, such as gastric cancer, glioblastoma and neuroblastoma, implicating that USP3 could be an effective target for targeted therapies. In this review, we retrace all the current researches of USP3, describe the structure of USP3, elucidate its functions in DNA damage, immune and inflammatory responses and the cell cycle, and summarize the important role of USP3 in multiple cancers and diseases.

Fig. 1. Timeline of USP3 research.

A number of studies of significance and relevance to disease and signalling pathways are listed to show the broad framework of USP3 research.

Fig. 2. The structure and domains of USP3.

Amino acids 1-121 form the Ub-binding domain Zinc finger and amino acids 159-511 comprise the catalytic domain of Ub-specific protease.

Fig. 3. Mutation features of USP3.

A Mutation type in different tumors of TCGA; B mutation site; C the 3D structure of the mutation site (G279C/S/Vfs).

Fig. 4. Regulation of USP3 expression in different levels.

The formation of a transcriptional activation complex involving ALYREF and MYCN and Smo promote the transcription of USP3 in the DNA level; related ceRNA network of USP3 and RNA-binding proteins regulate USP3 expression in the mRNA level; PEITC (Phenethylisothiocyanate, a DUB inhibitor) and PARP1 (poly-ADP-ribose polymerase 1, a positive role) can influence USP3 (drawn by Figdraw) in the protein level.