Regulation of Protein Degradation and Homeostasis by the Cytokine-Inducible Deubiquitinating Enzymes

Ubiquitin-proteasome system (UPS) is the major signaling pathway responsible for regulating protein turnover in cells. Deubiquitinating enzymes (DUBs) have an important role in this signaling pathway by eliminating ubiquitins from substrates and inhibiting proteasomal degradation to maintain cellular homeostasis. Based on the published data on cytokine-inducible DUBs including DUB-1, DUB-2, DUB-2A, DUB-1A and DUB-3, they play a pivotal role in the regulation of proliferative and apoptotic processes for immune cells. In this review, I discuss the importance of cytokine-inducible DUBs and the development of new therapeutic targets for these DUBs in immune-related diseases. Ubiquitin-proteasome system (UPS) is the major signaling pathway responsible for regulating protein turnover in cells. Deubiquitinating enzymes (DUBs) have an important role in this signaling pathway by eliminating ubiquitins from substrates and inhibiting proteasomal degradation to maintain cellular homeostasis. Based on the published data on cytokine-inducible DUBs including DUB-1, DUB-2, DUB-2A, DUB-1A and DUB-3, they play a pivotal role in the regulation of proliferative and apoptotic processes for immune cells. In this review, I discuss the importance of cytokine-inducible DUBs and the development of new therapeutic targets for these DUBs in immune-related diseases. Mini Review Regulation of Protein Degradation and Homeostasis by the CytokineInducible Deubiquitinating Enzymes Kwang-Hyun Baek* Department of Biomedical Science, CHA University, Gyeonggi-Do 13488, Republic of Korea Received: 22 February, 2018 Accepted: 27 March, 2018 Published: 28 March, 2018 *Corresponding author: Kwang-Hyun Baek, Department of Biomedical Science, CHA University, Gyeonggi-Do 13488, Republic of Korea


Introduction
Ubiquitination is one of versatile post-translational modifi cations (PTMs), and it controls almost every aspect of cellular homeostatic processes in eukaryotic cells [1]. Therefore, it is pivotal to regulate the proper ubiquitin signaling for homeostatic maintenance [2]. In general, proteins degraded by the proteasome system are initially conjugated to the ubiquitin (Ub), a small polypeptide of 76 amino acids, which serves as a signal [3,4]. In a sequential events regulated by a cascade of ubiquitin-conjugating enzymes, ubiquitin is conjugated to specifi c substrates. The fi rst class of enzymes involved in this cascade reaction is called the ubiquitin activating enzymes (E1). This E1-Ub complex then undergoes a reaction with one of ubiquitin carrier proteins (E2), in which the bound ubiquitin is transferred from E1 to E2. E2, in conjunction with an ubiquitin-ligase enzyme (E3), mediates the fi nal transfer of ubiquitin to the target protein [5,6]. Covalent attachment of ubiquitin to target proteins induces their degradation by the 26S proteasome [7].
It has been identifi ed that there are seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) in the peptide sequence of ubiquitin, and ubiquitin chains targeted for substrate proteins are formed on these residues serving as acceptors for another ubiquitin [8]. Different types of polyubiquitin chains generate various outcomes of the target protein [9]. When the K48-linked polyubiquitin chain, the most abundant linkage type, is established on target proteins, the 26S proteasome recognizes and degrades the polyubiquitinated protein [10].
In contrast, K63-linked polyubiquitination modifi es diverse protein functions including DNA repair and endocytosis but does not lead to proteasomal degradation [11,12]. However, it is still not fully understood how different types of polyubiquitin chains are decoded in a cellular system yet. Deubiquitinating enzymes (DUBs) play a role in removing ubiquitin molecules from substrates and have diverse roles in cellular processes [13]. It has been suggested that approximately 100 DUBs are encoded in the human genome [2], and they are classifi ed into distinct subfamilies depending upon the organization of the catalytic domain. In general, they have been grouped into two main classes: cysteine protease and metalloprotease [14]. domains for catalytic activity of the enzyme, but also their primary amino acid sequences [21,22]. It was demonstrated that DUB-1 is induced by cytokines IL-3, IL-5 and GM-CSF in B-lymphocytes, and it was found that DUB-1 is involved in cell growth arrest in the G1 phase of the cell cycle [19].
Interestingly, it was demonstrated that DUB-2 is induced by IL-2 only in T-lymphocytes [20]. And Dub-2 knock-out mice showed embryonic lethality and growth inhibition [25]. In addition, DUB-3 identifi ed in human chorionic villi is induced by IL-4 and IL-6 and is involved in the regulation of cell growth and survival [23][24][25]. However, most of their substrates for these cytokine-inducible DUBs have not been found yet and their deubiquitinating enzyme activity has been mostly tested only in vitro. Since the enzymatic activity of these DUBs has been tested in vitro with the long period of induction to cleave the ubiquitin, it is not possible to know how fast the enzymatic activisty appears.

Conclusions
Spatial and temporal elimination of misfolded and damaged proteins is required to prevent the accumulation of toxic proteins, which can lead to diverse diseases including cancer and immune diseases [7]. However, it is not clear how a cell determines whether proteins targets should be degraded by the UPS or not. Given the signifi cance of ubiquitin signaling in human diseases, important directions for future studies will include the analysis of underlying mechanisms that regulate the UPS for developing therapeutic implications for cancer and other immune diseases.
Even though cytokine-inducible DUBs are known to be involved in the regulation of cell proliferation and apoptosis, their DUB inhibitors have not been identifi ed or developed for therapeutic purposes yet. Therefore, important directions for future studies will include identifi cation of their substrates and underlying molecular mechanisms, and delineation of their molecular structures to provide us a novel way of developing therapeutic drugs especially for disease like cancer and immune diseases. Figure 1: The ubiquitin-proteasome system. There are two steps in this system: ubiquitination and target protein degradation. Regulation of proteasome-mediated protein degradation is carried out by a series of Ub-conjugating enzymes (ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2, and ubiquitin ligase E3) and deubiquitinating enzymes (DUBs). Ubiquitinated protein substrates are degraded by the 26S proteasome.