Molecular Mechanisms of DUBs Regulation in Signaling and Disease

Abstract

The large family of deubiquitinating enzymes (DUBs) are involved in the regulation of a plethora of processes carried out inside the cell by protein ubiquitination. Ubiquitination is a basic pathway responsible for the correct protein homeostasis in the cell, which could regulate the fate of proteins through the ubiquitin–proteasome system (UPS). In this review we will focus on recent advances on the molecular mechanisms and specificities found for some types of DUBs enzymes, highlighting illustrative examples in which the regulatory mechanism for DUBs has been understood in depth at the molecular level by structural biology. DUB proteases are responsible for cleavage and regulation of the multiple types of ubiquitin linkages that can be synthesized inside the cell, known as the ubiquitin-code, which are tightly connected to specific substrate functions. We will display some strategies carried out by members of different DUB families to provide specificity on the cleavage of particular ubiquitin linkages. Finally, we will also discuss recent progress made for the development of drug compounds targeting DUB proteases, which are usually correlated to the progress of many pathologies such as cancer and neurodegenerative diseases.

Ubiquitin Specific Protease 29 Functions as an Oncogene Promoting Tumorigenesis in Colorectal Carcinoma

“…USPs are cysteine proteases that are responsive to various electrophiles and have been targeted as therapies for various cancers [ 11 ]. Therefore, it is highly desirable to characterize which USPs are critical to each cancer type to enable precision cancer treatment.…”

Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

“…There are two major classes of DUBs, cysteine proteases and metalloproteases ( 42 , 43 ). The former of these classes is further broken down into six families of proteins, based on sequence conservation and domain architecture ( 44 ). However, all DUBs in this class utilize a catalytic triad composed of an active site cysteine residue, along with a histidine and (in most cases) an asparagine or aspartate, to catalyze the hydrolysis of the ubiquitin linkages ( 43 ).…”

“…Having inhibitors to this class of DUBs enabled faster identification and characterization of new members, thus resulting in better knowledge of their impact on cellular physiology and how they might be used in the manipulation of therapeutic systems ( 49 ). The six families of cysteine protease DUBs include the ubiquitin C-terminal hydrolase (UCH), ubiquitin-specific protease (USP), ovarian tumor (OTU), Machado–Josephin domain (MJD), K48 polyubiquitin-specific MINDY domain families, as well as the newest-discovered DUB family, zinc finger with UFM1-specific peptidase domain, named for its founding protein member ( 44 ).…”

“…The four members of the MJD family (ataxin 3 [ATXN3], ATXN3L, Josephin domain-containing 1, and Josephin domain-containing 2) all present a highly conserved catalytic Josephin domain, which contains two ubiquitin binding sites as well as two conserved histidines, along with the catalytic cysteine, that are necessary for catalysis ( 44 , 62 ). This family is named for Machado–Josephin disease, a neurological disorder caused by an expansion of the CAG repeat motif in ATXN3, producing polyglutamine and causing protein misfolding and aggregation ( 63 ).…”

Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code

“…However, certain DUBs require Ub-binding or modulation to form their active conformation. In a cellular environment, DUB activity is tightly regulated because uncontrolled activation can be detrimental for cells ( Reyes-Turcu et al, 2009 ; Li and Reverter, 2021 ). Herein, PTMs are a critical approach to regulate the activity and specificity of DUBs, and also play an important role in DUBs-related diseases.…”