TY - JOUR
AU - Ramakrishna, Suresh
AB - Abstract Post-translational modification by ubiquitin molecules is a key regulatory process for stem cell fate determination. Ubiquitination and deubiquitination are the major cellular processes used to balance the protein turnover of several transcription factors that regulate stem cell differentiation. Deubiquitinating enzymes (DUBs), which facilitate the processing of ubiquitin, significantly influence stem cell fate choices. Specifically, DUBs play a critical regulatory role during development by directing the production of new specialized cells. This review focuses on the regulatory role of DUBs in various cellular processes, including stem cell pluripotency and differentiation, adult stem cell signaling, cellular reprogramming, spermatogenesis, and oogenesis. Specifically, the identification of interactions of DUBs with core transcription factors has provided new insight into the role of DUBs in regulating stem cell fate determination. Thus, DUBs have emerged as key pharmacologic targets in the search to develop highly specific agents to treat various illnesses. Post-translational modification, Ubiquitination, Deubiquitination, Deubiquitinating enzymes, Pluripotency, Differentiation, Spermatogenesis, Oogenesis Significance Statement The review is written from a unique perspective in overseeing the regulatory role of deubiquitinating enzymes in stem cells. A great attention has been given to the physiological role of ubiquitination system in regulating pluripotency of embryonic stem cells. However, the reversal of ubiquitination by deubiquitinating enzymes plays an equally important role in the regulation of levels of expression of the stemness-related proteins by preventing its ubiquitination. This is timely topic, given that this is the first review article attempting to discuss the accumulated evidence suggesting the critical role of deubiquitinating enzymes in regulating stem cell fate determination process such as maintenance of pluripotency, differentiation, cellular reprogramming, spermatogenesis, and oogenesis. Beyond this, the review provide us the clue for the remaining challenges in developing DUBs as targets for stem cell therapeutics. Introduction Stem cells have the unique capability to differentiate into different cell types. At the time of division, every stem cell has the ability to either develop into a specific cell type or to remain a stem cell. Numerous studies have shown that stem cell pluripotency, differentiation, and cellular reprogramming are regulated by various transcription factors [1]. Post-translational modifications (PTMs) are important for directing different cellular processes and contribute an additional level of protein regulation. A key mechanism by which PTMs are regulated is ubiquitination, which relies upon deubiquitination by deubiquitinating enzymes (DUBs). In embryonic stem cells (ESCs), self-renewal regulation and pluripotency factors have been mainly examined at the transcriptional level and information about the effects of DUBs on their function is still lacking. This review addresses the interactions of candidate DUBs with several stemness-related proteins and the regulatory role of DUBs in various cellular processes, such as stem cell pluripotency and differentiation, adult stem signaling, cellular reprogramming, spermatogenesis, and oogenesis. Ubiquitin Proteasome Pathway Ubiquitination is a PTM in which ubiquitin is coupled to a protein substrate in a reversible manner. This coupling helps regulate the structural stability and function of the modified protein. A series of events catalyzed by three classes of enzymes is required for an ubiquitin molecule to be attached to a target protein. These classes are: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3) [2, 3]. Major players in the ubiquitin proteasomal pathway (UPP) and the mechanisms of action of various DUBs are depicted in Figure 1A. Figure 1 Open in new tabDownload slide Overview of the ubiquitin-proteasome pathway and catalytic functions of DUBs. (A): Ubiquitin-proteasome pathway. In the first step, the E1 enzyme utilizes ATP and is phosphorylated. The phosphorylated E1 enzyme forms a thioester bond with the ubiquitin molecule for activation. Second, the ubiquitin molecule is conjugated with the E2 enzyme via thioester linkage. Finally, the E3 enzyme receives the ubiquitin molecule and transfers it to the target protein. Proteins can be subjected to either ubiquitination or polyubiquitination, based on the target protein expression. (B): Different catalytic activities of DUBs. DUBs can undo ubiquitin conjugation by cleaving the bond between ubiquitin-ubiquitin and ubiquitin-substrate complexes, edit ubiquitin chains to remove one or more ubiquitin moieties, and recycle ubiquitin molecules in the ubiquitin-proteasome pathway. Abbreviation: DUBs, deubiquitinating enzymes. Figure 1 Open in new tabDownload slide Overview of the ubiquitin-proteasome pathway and catalytic functions of DUBs. (A): Ubiquitin-proteasome pathway. In the first step, the E1 enzyme utilizes ATP and is phosphorylated. The phosphorylated E1 enzyme forms a thioester bond with the ubiquitin molecule for activation. Second, the ubiquitin molecule is conjugated with the E2 enzyme via thioester linkage. Finally, the E3 enzyme receives the ubiquitin molecule and transfers it to the target protein. Proteins can be subjected to either ubiquitination or polyubiquitination, based on the target protein expression. (B): Different catalytic activities of DUBs. DUBs can undo ubiquitin conjugation by cleaving the bond between ubiquitin-ubiquitin and ubiquitin-substrate complexes, edit ubiquitin chains to remove one or more ubiquitin moieties, and recycle ubiquitin molecules in the ubiquitin-proteasome pathway. Abbreviation: DUBs, deubiquitinating enzymes. Ubiquitin is a small regulatory protein that is attached to its substrate as a monomer or a polymer. It contains seven lysine (K) residues, K-6, K-11, K-27, K-29, K-33, K-48, and K-63. Each of these residues can be linked to others, thus forming polyubiquitin chains consisting of sequentially linked ubiquitin molecules [4]. Of all the possible polyubiquitin chains, the chains formed by K-48 and K-63 linkage are the most common and have thus been well-studied. For example, polyubiquitination via K-48 directs the target protein for degradation by the 26S proteasome, whereas polyubiquitination via K-63 regulates signal transduction and protein activity [4]. The functions of the other K-6, K-11, K-27, K-29, and K-33 polyubiquitin chains are summarized in Supporting Information Figure 1. Deubiquitination Deubiquitination is the process of dissociating the ubiquitin-substrate complex and the ubiquitin-ubiquitin covalent links and is carried out by DUBs. Deubiquitination is the reverse of ubiquitination and thus plays an important counterbalance in homeostasis by releasing the ubiquitin conjugates [5]. DUBs are involved in three important cellular activities, namely: recycling and conversion of ubiquitin from a previous ubiquitination event, editing and rearranging the ubiquitination process to modify the target protein accordingly, and removal of nonessential ubiquitin molecules [5] (Fig. 1B). Approximately 100 different types of DUBs have been identified in the human genome. DUBs are classified into six broad categories: ubiquitin-specific processing protease (USP/UBP), ubiquitin carboxy-terminal hydrolase (UCH), Jad1/Pad/MPN-domain-containing metalloenzyme, Otu-domain ubiquitin aldehyde binding protein, Ataxin-3/Josephin, and monocyte chemotactic protein-induced protease [5]. DUBs in Stem Cell Pluripotency and Differentiation PTM of stemness-associated proteins is a critical factor in determining stem cell fate. In particular, protein turnover and the balancing action of DUBs, which govern the ubiquitination and deubiquitination equilibrium for stemness-related proteins, plays a major role in stem cell maintenance and differentiation. To achieve stemness efficiency and attain efficient differentiation, the ubiquitination and deubiquitination molecular switches must be highly coordinated with one another. The ubiquitin-proteasome system (UPS) has an undisputed essential role in stem cell pluripotency and differentiation [6]. However, recent studies of the DUBs USP9X, USP22, USP44, and Psmd14 have shown that DUBs are equally important in maintenance of pluripotency in stem cells. USP9X is one of the largest members in the USP family and is highly expressed in stem cells in vivo, including neural stem cells (NSCs) and preimplantation blastomere embryos [7]. USP9X is also expressed in human and mouse stem cells, including ESCs, neuronal progenitors (NPs), NSCs, hematopoietic stem cells (HSCs), and adult epidermal stem cells [8]. Intriguingly, USP9X was found to drive the differentiation and proliferation of muscle stem cells by regulating the mTOR pathway [9]. USP22 is a deubiquitinating subunit in the SAGA-mDUB complex. A recent study showed that USP22-mediated deubiquitination of Hairy and Enhancer of split 1 (Hes1) is important for neuronal differentiation in the developing brain [10]. Hes1 expression has been shown to oscillate in mouse ESCs and NSCs. This oscillation contributes to stem cell pluripotency and differentiation fate [11]. However, USP22 dampens this oscillation through deubiquitination. Furthermore, USP22-mediated deubiquitination has been shown to shorten the half-life of Hes-1 due to rapid protein degradation, resulting in delayed auto-repression and dampened oscillation, eventually leading to increased neuronal differentiation [10]. Moreover, USP22-mediated deubiquitination of uH2B is essential for regulating transcriptional elongation on interferon regulatory factor 1, a target gene of STAT1. Silencing of USP22 blocked recruitment of polyadenylation factor CPSF73 and disrupted serine 2 phosphorylation of RNA polymerase II, resulting in reduced 3′-end cleavage/polyadenylation. Thus, USP22 is considered to be a putative cancer stem cell marker [12]. In addition, USP22 is required for ESCs to differentiate accurately into all three germ layers [13]. USP22 also localizes to the Sox2 promoter and negatively regulates Sox2 transcription by catalyzing H2B deubiquitination during ESC differentiation [13]. Thus, USP22 is required during ESC conversion all the way through the self-renewal state to lineage-specific differentiation. USP44 is a well-known mitotic spindle checkpoint regulator in differentiated cells. During mitosis, USP44 deubiquitinates Cdc20 and regulates anaphase initiation [14]. Genome scale location analysis has shown that USP44 is a direct target of Oct4 [15]. Moreover, recent data has indicated that USP44 is downregulated during ESC differentiation and is directly involved in the regulation of stem cell differentiation [16]. Histone H2B monoubiquitination at the 120th lysine residue (H2Bub1) increases during differentiation of mouse and human ESCs and is regulated by RNF20, a E3 ubiquitin ligase [17]. During ESC differentiation, USP44 silencing was shown to lead to increased levels of H2Bub1 [16]. Cumulatively, this evidence suggests that ESC differentiation requires an optimal level of expression of USP44. Psmd14 is a component of the 19S proteasome lid and was recently identified as essential for stem cell maintenance. Specifically, Psmd14 expression is high in ESCs, while its expression level decreases during differentiation [6]. Psmd14 silencing has been shown to result in a significant reduction in Oct4 expression, resulting in abnormal ESC morphology. Altogether, these findings suggest that several DUBs play major roles in the maintenance of stem cell pluripotency and differentiation. DUBs in Adult Stem Cells The inhibitor of DNA binding (ID) family is comprised of ID1, ID2, ID3, and ID4, which heterodimerize with basic helix-loop-helix (bHLH) transcription factors to inhibit DNA binding of bHLH proteins [18]. ID proteins are vital for development by preventing premature differentiation of stem cells [19]. USP1 has been reported to deubiquitinate and stabilize ID1, ID2, and ID3, thus regulating the mesenchymal stem cell (MSC) state in osteosarcoma [20]. Upregulation of USP1 leads to the inhibition of osteogenic differentiation, while USP1 deficiency results in osteogenic differentiation and cell cycle arrest. Thus, USP1 has a carcinogenic effect and mediates tumorigenesis by disrupting MSC differentiation. Herpesvirus-associated ubiquitin-specific protease (HAUSP or USP7)-mediated deubiquitination was recently reported to prevent the degradation of repressor element 1 silencing transcription factor (REST), thereby facilitating the maintenance of neural stem and progenitor cells [21]. USP7 makes contact with and stabilizes REST by preventing SCFβ-TrCP-associated ubiquitination, thus improving the maintenance of stemness [21]. The triplication of the Usp16 gene decreases the self-renewal efficiency of HSCs and the expansion of NPs, mammalian epithelial cells, and fibroblasts in the Ts65Dn Down syndrome (DS) mouse model [22]. Also, Usp16 can cleave ubiquitin from H2A at K-119; through this reaction, multiple somatic tissues are maintained. Downregulation of Usp16 partially recovers the proliferation defects of DS fibroblasts, while overexpression of USP16 inhibits the expansion of fibroblasts and postnatal NPs [22]. Thus, USP16 antagonizes self-renewal and senescence pathways in DS. USP21 deubiquitinates the transcription factor GATA3, which is essential for HSC maintenance [23]. However, the Usp21 knockout mouse does not exhibit any significant changes in HSC function or hematopoiesis progression [24]. Thus, unlike GATA3, USP21 is not required for the maintenance of HSC functions. Another study demonstrated that USP21 deubiquitinates RIG-1, an essential protein in antiviral immune defense. However, chimeric mice with USP21-deficient hematopoietic cells exhibited splenomegaly development and were protected from VSV-induced lethality [24]. Taken together, these data indicate that USP21 plays a critical role in hematopoiesis and immunity. DUBs in Cellular Reprogramming Recent findings have demonstrated that some DUBs are involved in stem cell regulation and influence cellular reprogramming. For example, USP22, USP44, and Psmd14 influence stem cell transcription factors during cellular reprogramming (Supporting Information Fig. 2A). Moreover, Psmd14 silencing leads to significantly decreased levels of Oct4 and aberrant ESC morphology. Additionally, somatic cells (mouse embryo fibroblasts) depleted of Psmd14 were unable to reprogram and generate iPSCs, suggesting that Psmd14 plays a critical role in cellular reprogramming [6]. USP22 is considered a potential cancer stem cell marker gene based on its aggressive metastatic cellular behavior and resistance to therapy [25]. The USP22 locus has been shown to be readily transcribed in human ESCs and iPSCs [26] and has also been shown to be vital for mouse embryonic development [25]. Additionally, USP22 is essential for the regulation of the core pluripotency factors c-Myc and Sox2 [27]. Specifically, USP22 is a cofactor for the transcription of MYC target genes [27]. In contrast, USP22 acts as a transcriptional repressor of the Sox2 promoter [13]. Along with the histone H3 lysine 4 trimethyl epigenetic marker, KLF4 is also recruited to the USP22 promoter [26]. A genome-scale localization analysis identified several DUBs that bind to the promoter regions of core embryonic transcription factors such as Oct4, Sox2, and Nanog [15]. Specifically, USP25, USP44, USP49, and USP7 bind to the Sox2 promoter; USP44 and USP7 bind to the Oct4 promoter; and USP10, USP16, USP3, USP37, USP44, and USP7 bind to the Nanog promoter [5] (Supporting Information Fig. 2B). The finding that several DUBs regulate core stem cell transcription factors demonstrates the importance of DUBs during cellular reprogramming. However, the specific mechanisms by which DUBs regulate Oct4-, Sox2-, and Nanog-driven transcription are not yet fully understood, nor are the precise roles of each DUB in stem cell differentiation and cellular reprogramming. DUBs in Germ Cells Sexual development concludes in the generation of functional gametes. Spermatozoa and oocytes arise from primordial germ cells (PGCs). The process by which PGCs develop into sperm or egg cells differs from species to species [28] and is regulated by several DUBs. DUBs in Spermatogenesis Spermatogenesis is a key process in which mature spermatozoa are produced from male PGCs through mitosis, meiosis, and cell differentiation. Generally, male germ cells harbor extensive intracellular ubiquitination. USP enzymes have been reported to have prominent roles during spermatogenesis from gonocytes to spermatids. Inactivation of USP enzymes causes abnormal progression of male germ cells, leading to infertility [29]. USPs have also been implicated in a number of physiological processes in different stages of spermatogenesis, namely gonocyte and spermatogonial development, meiosis regulation, and spermiogenesis [29]. USP2a and USP2b are two isoforms of USP2 that have been observed in the rat testis [30]. In general, USP2a is expressed more highly during the late elongation stage for spermatids and exhibits differential localization. In particular, significant nuclear expression of USP2a is observed in steps 16-19 spermatids. In contrast, USP2b is more abundant in steps 18-19 spermatids, and is expressed in the extranuclear space [31]. USP2-knockout mice show normal physical appearance and body weight. However, although USP2-knockout mice show normal counts of testicular spermatids and epididymal spermatozoa, abnormal aggregation of elongated spermatids was observed, leading to multinucleated cells in some tubules, and fertility defects [32]. Ubiquitin-specific processing protease-y (UBPy), otherwise known as USP8, is highly expressed in the testis and brain. UBPy has a prominent function in acrosome biogenesis and interacts with mouse testis-specific DnaJ, which is known for its role in acrosome formation [33]. Moreover, UBPy can be observed in the spermatids of wobbler mice in the first wave of spermatogenesis, in contrast to those of normal mice. Additionally, UBPy is present in an insoluble fraction in wobbler mice and a soluble fraction in wild-type mice [34]. UBPy is expressed on the surface of acrosomic vesicles in normal mice. In contrast, coalescence does not take place in the acrosomic vesicles to produce a functional acrosome in wobbler mice. Diffuse expression of UBPy has been observed in the cytoplasmic or perinuclear area of round spermatids [35]. Furthermore, inactivation of Ubpy leads to embryonic lethality [36]. Based on the key regulatory role of UBPy in cellular events such as vesicle trafficking, endosomal sorting, and endocytic vesicle maintenance, Ubpy is considered to be a marker of acrosome biogenesis [36]. In humans, the Y chromosome has been reported to harbor several genes that regulate spermatogenesis [37]. USP9Y is located within a small section of the azoospermia factor region on the Y chromosome and is associated with severe spermatogenetic failure. The effects of USP9Y deletion and its association with spermatogenesis are controversial. Initially, it was reported that USP9Y deletion causes infertility (oligospermia) and spermatogenetic failure [38]. Later, partial deletion of the USP9Y region in men was linked with a milder infertility phenotype [39]. However, later clinical studies did not observe any correlation between USP9Y and oligospermia [40], and further examination of complete deletion of the USP9Y region did not reveal any association with spermatogenetic defects. Thus, USP9Y is not presently considered to play a significant role in spermatogenesis. The downregulation of Usp14 in Homozygous ataxia (axJ) mice was found to alter their reproductive potential [41]. Specifically, this downregulation resulted in two-tailed spermatozoa and decapitated sperm bodies in axJ mice. Furthermore, the mean weight of wild-type mice was twice that of axJ mice, and the mean sperm count of axJ mice was significantly lower than that of wild-type mice. Histological reports also confirmed that Usp14-deficient testes show abnormal spermatogenesis and the presence of degenerating germ cells. Hence, Usp14 regulates spermatid differentiation in the male reproductive system [42]. USP26 is highly expressed in spermatogonia types A and B, preleptotene spermatocytes, round spermatids, and at the blood-testis barrier [43]. USP26 regulates androgen receptor hormone-mediated spermatogenesis and steroid production [44]. Almost 20 mutations in USP26 have been found to be associated with male infertility. Three mutations periodically appear in both fertile and infertile groups, c.363_364insACA, c.494T > C, and c.1423 > T. All three mutations are associated with oligozoospermia and azoospermia. However, studies of these mutations have yielded conflicting results. One report observed significant correlations between these mutations and male fertility [45], whereas another did not [46]. USP25 is expressed in the adult mouse testis and in spermatocytes I and II in the testis. These findings imply that USP25 may regulate protein turnover [47]. Conversely, USP42 is expressed at high levels in the mouse testis, thymus, lung, and brain. The expression level is further increased at the round-spermatid stage and slightly decreased at the condensing-spermatid stage [48]. The complete biological functions of these DUBs have not yet been analyzed. Among the UCHs, Uchl-1 and Uchl-3 show different expression patterns during the different stages of spermatogenesis [49]. An increase in apoptotic spermatocytes was found to be due to the overexpression of Uchl-1 in the mouse testis, leading to spermatogenesis arrest and increased expression of activated caspase-3. This finding suggests that Uchl-1 is an apoptotic factor regulating apoptotic stress during spermatogenesis. The primary action of Uchl-3 takes place during meiotic differentiation of spermatocytes into spermatids, while Uchl-1 and Uchl-4 are expressed in spermatogonia [50]. Additionally, Uchl-5 is expressed in spermatocytes and spermatids during spermatogenesis [50]. The human cylindromatosis gene (CYLD) is found on chromosome 16q12.1 and encodes the cylindromatosis protein. CYLD-knockout mice fail to produce offspring and have abnormalities in the seminiferous tubules [51]. Moreover, CYLD-knockout mice show disorganized seminiferous epithelium and abnormal germ cell development, leading to attenuation of the early wave of germ cell apoptosis [51]. Loss of CYLD leads to constitutive activation of NF-κB in germ cells, resulting in aberrant expression of anti-apoptotic Bcl-2 members [52]. CYLD interacts with and deubiquitinates receptor-interacting protein 1 (RIP1), primarily by targeting IKK and NF-κB. Loss of CYLD results in accumulation of ubiquitinated RIP1, which in turn leads to the activation of IKK and NF-κB [53]. Thus, CYLD has a critical role in spermatogenesis, germ cell apoptosis, and male fertility [51]. DUBs in Oogenesis DUBs in the UCH family play important roles in oocyte maturation, fertilization, and development in various species. Regulation of protein degradation is essential for oocyte maturation [54]. The cumulus oophorus surrounds the oocyte to regulate the access of spermatozoa during fertilization. During oocyte maturation, the development of cumulus cells is inhibited by proteasomal inhibitors [55]. The inhibition of UCH action has been shown to generate large polar bodies, signaling an interruption in spindle localization of the microfilament cytoskeleton in the oocyte cortex [54]. Moreover, UCHL1 has been reported to regulate the activity of microfilament-regulating proteins [56] and formin-2 proteins such as DIAPH3, which are degraded by UPP in cell division [57]. ARF1 activates proteasomal inhibitors, which increase poly-ADP ribosylation [58]. Other ARFs assist ADP-ribosyltransferases; this is important because ADP ribosylation regulates DNA repair, apoptosis, and cell signaling. Expression of a mutant variant of Arf1 (Arf1T31N) caused mouse oocytes to divide uniformly rather than expelling the first PB in meiosis [59]. Thus, UCHs reverse the effects of ARF6, which is regulated by ubiquitination [54]. Moreover, UCH1 and the relevant UCHs regulate actin and myosin microfilaments during PB extrusion [60]. Eventually, UCH inhibition during oocyte maturation leads to aneuploidy in the resulting embryo [61]. UCHL3 interacts in the polyspermy defense mechanism at the oolemma due to its availability and aggregation in the oocyte cortex [62]. Furthermore, sperm acrosomal UCHL3 is involved in sperm-zona pellucida (ZP) interactions and controls polyspermy in pigs. To prevent polyspermic fertilization, oocytes rely on plasma membrane depolarization, ZP hardening, and exocytosis of cortical granules. After sperm fusion with the oolemma, instantaneous transitions in both the ZP and the plasma membrane take place [63]. UCHL1 inhibition in bovine oocytes during maturation damages cortical granule exocytosis and boosts polyspermy rates [64]. There is also evidence in porcine zygotes indicating that ubiquitin aldehyde increases polyspermy [62]. Furthermore, in zona-intact oocytes, the fertilization rate is decreased due to ooplasmic UCH inhibition by UBAL microinjection [65]. These findings indicate that UCHL1 influences postfertilization modifications of the cortical cytoskeleton, oolemma, and ZP. While the UCH expression motifs appear to be conserved between rodents and primates, their mechanisms of action may vary. High expression of proteasomal subunits of the ubiquitin system appears to be a common characteristic in early embryos and in mammalian oocytes. Thus, the findings discussed above clearly demonstrate the significance of UCHs in oocyte maturation and fertilization, and reveal a critical maternal effect of the Uchl1 gene. Conclusion DUBs have many essential regulatory functions in stem cells. Specifically, DUBs can regulate proteolysis by neutralizing the action of the ubiquitination system on specific substrates. As the levels of most proteins are regulated by the ubiquitination-deubiquitination counterbalance, interest in the UPS system has expanded. However, DUBs are considered to be attractive stem cell therapeutic targets due to the extensive available molecular structures and recent advances in small molecule-based inhibitors specifically targeting DUBs. However, much research still remains to be performed to corroborate and expand the application of these inhibitors to the clinic. The UPS system is essential for maintaining cellular homeostasis; thus, detection of specific inhibitor molecules by the various DUBs may offer a novel mechanism for treating some diseases. The removal of ubiquitin moieties by DUBs has broad implications on the regulation of stem cell pluripotency and differentiation, cellular reprogramming, spermatogenesis, and oogenesis (Fig. 2). Thus, DUBs have emerged as promising pharmacologic targets for developing highly specific agents for treating diseases. The work discussed here promises to accelerate future attempts for developing efficient screening methods. Figure 2 Open in new tabDownload slide Roles of DUBs in the regulation of stem cell pluripotency and differentiation, cellular reprogramming, spermatogenesis, and oogenesis. Various DUB families involved in the respective cellular processes are represented in the triangle. Figure 2 Open in new tabDownload slide Roles of DUBs in the regulation of stem cell pluripotency and differentiation, cellular reprogramming, spermatogenesis, and oogenesis. Various DUB families involved in the respective cellular processes are represented in the triangle. Acknowledgments We thank all members of the Suri laboratory for helpful discussions. We regret that we were unable to cite more relevant studies due to space considerations. This study was supported by a grant from the National Research Foundation of Korea (201500000002885, 2015H1D3A1036065, and 2015R1D1A1A01060907). Author Contributions A.P.C., B.S., K.S.K.: conception and design, manuscript writing; H.B.K., B.S., S.R.K.: conception and design, financial support, manuscript writing. Disclosures The authors have no potential conflicts of interest to disclose. References 1 Cai N , Li M, Qu J et al. Post-translational modulation of pluripotency . J Mol Cell Biol 2012 ; 4 : 262 – 265 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Hershko A , Heller H, Elias S et al. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown . J Biol Chem 1983 ; 258 : 8206 – 8214 . 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Google Scholar Crossref Search ADS PubMed WorldCat Author notes A.P.C. and B.S. contributed equally to this work. © 2016 AlphaMed Press This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Concise Review: Fate Determination of Stem Cells by Deubiquitinating Enzymes
JF - Stem Cells
DO - 10.1002/stem.2446
DA - 2017-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/concise-review-fate-determination-of-stem-cells-by-deubiquitinating-5eD81wb3uF
SP - 9
EP - 16
VL - 35
IS - 1
DP - DeepDyve
ER -