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

Abstract

Ubiquitin signaling is a conserved, widespread, and dynamic process in which protein substrates are rapidly modified by ubiquitin to impact protein activity, localization, or stability. To regulate this process, deubiquitinating enzymes (DUBs) counter the signal induced by ubiquitin conjugases and ligases by removing ubiquitin from these substrates. Many DUBs selectively regulate physiological pathways employing conserved mechanisms of ubiquitin bond cleavage. DUB activity is highly regulated in dynamic environments through protein–protein interaction, posttranslational modification, and relocalization. The largest family of DUBs, cysteine proteases, are also sensitive to regulation by oxidative stress, as reactive oxygen species (ROS) directly modify the catalytic cysteine required for their enzymatic activity. Current research has implicated DUB activity in human diseases, including various cancers and neurodegenerative disorders. Due to their selectivity and functional roles, DUBs have become important targets for therapeutic development to treat these conditions. This review will discuss the main classes of DUBs and their regulatory mechanisms with a particular focus on DUB redox regulation and its physiological impact during oxidative stress.

Epigenetic modification regulates tumor progression and metastasis through EMT (Review)

“…The synergistic effect of Dubs recognition and Ub hydrolysis creates a dynamic network that controls the distribution of different ubiquitin signals, which in turn regulates numerous biological processes within the cancer cell ( 142 ). Approximately 103 Dubs have been recognized in the human genome, and they can be divided into six families according to their sequence and the sequence of conserved regions: USPs (ubiquitin-specific proteases) such as USP2, USP6, USP7, USP8, USP11, USP15, USP16, USP21, USP 28, USP35; UCHs (ubiquitin C-terminal hydrolysis enzymes) such as UCH-L1, UCH-L3, UCH-L5; MJDs (Machado-Joshphin domain-containing proteases) such as JosD1, JosD1; OUTs (ovarian cancer proteases) such as A20, OTUB2, TRABIO; SENPs (motif-interacting with ubiquitin-containing novel DUB family), such as SENP1, SENP2, SENP8; JAMMs (JAB1, MPN, MOV34 family) such as AMSH ( 143 ).…”

Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

“…Depending on their enzymatic cleavage mechanism, DUBs are classified into two types: cysteine protease and metalloprotease. The cysteine protease DUBs include the remaining eight subfamilies, excluding the JAMM family; they cleave the isopeptide bond of lysine residues ubiquitinated by catalytic cysteine [ 86 ]. All metalloprotease DUBs are involved in cleaving the isopeptide bond of lysine residues by a catalytic serine and a zinc ion cofactor [ 87 , 88 ].…”

Helicobacter pylori-induced reactive oxygen species direct turnover of CSN-associated STAMBPL1 and augment apoptotic cell death

“…ROS-inducing chemotherapeutic agents are used for the therapeutic treatment of cancer patients with the aim of causing apoptotic cell death of cancer cells [ 13 ]. The genotoxic stress response triggered by ROS clearly activates cellular signalling pathways and the activity of DUBs and E3 ligases [ 14 ]. In addition, microbial pathogens such as H. pylori , which colonises the gastric mucosa, initiates the production of ROS in the cells of the gastric mucosa [ 15 ] and induces cell line-dependent apoptotic cell death [ 16 – 19 ].…”