Deubiquitinating Enzymes and Bone Remodeling

Guo, Yu-chen; Zhang, Shi-wen; Yuan, Quan

doi:https://doi.org/10.1155/2018/3712083

Stem Cells International

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Exogenous and Endogenous Stem Cells for Skeletal Regeneration

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Volume 2018 | Article ID 3712083 | https://doi.org/10.1155/2018/3712083

Deubiquitinating Enzymes and Bone Remodeling

Yu-chen Guo,¹Shi-wen Zhang,¹and Quan Yuan¹

Academic Editor: Bo Yu

Received29 Mar 2018

Accepted29 May 2018

Published08 Jul 2018

Abstract

Bone remodeling, which is essential for bone homeostasis, is controlled by multiple factors and mechanisms. In the past few years, studies have emphasized the role of the ubiquitin-dependent proteolysis system in regulating bone remodeling. Deubiquitinases, which are grouped into five families, remove ubiquitin from target proteins and are involved in several cell functions. Importantly, a number of deubiquitinases mediate bone remodeling through regulating differentiation and/or function of osteoblast and osteoclasts. In this review, we review the functions and mechanisms of deubiquitinases in mediating bone remodeling.

1. Introduction

The human skeleton undergoes continuous bone remodeling throughout a lifetime [1]. This process initiates with the destruction of mineralized bone, followed by the formation and mineralization of a new bone matrix [1, 2]. This critical process adapts bone architecture and strength to mechanical needs as well as growth. Meanwhile, it repairs microdamage of bone structure and maintains calcium homeostasis [1, 2]. Thus, bone remodeling is pretty important to general health.

To maintain bone homeostasis, bone remodeling is carried out by three main cell lineages: osteoclasts, multinucleated cells differentiate from macrophages and monocytes in the human hematopoietic lineage, resorb mineralized bone, and initiate the bone remodeling cycle [3]; osteoblasts, differentiate from mesenchymal stem cells (MSCs), deposit, and mineralize a new bone matrix [4]; osteocytes, which are the most common cells divided from osteoblasts, serve as a sensing and information transfer system [2]. These cells constitute the basic multicellular unit (BMU) that carries out the bone remodeling cycle. Based on current knowledge, bone remodeling mainly involves the following phases: formation of osteoclasts and resorption of bone, which initiates the cycle; completion of bone resorption followed by recruitment and differentiation of MSCs into osteoblasts; and bone formation mediated by osteoblasts [2]. Thus, the differentiation, function, and interaction of these BMU cells are critical to regulate bone remodeling and maintain bone homeostasis.

Osteoclasts that trigger the bone remodeling cycle are formed by the fusion of mononuclear progenitors in osteoclastogenesis [2]. They exist in a motile state during which they migrate from the bone marrow to the resorption site or a resorptive state performing their bone resorption function [5]. Osteoclasts are derived from the hematopoietic lineage and regulated by several factors [6]. Among these factors, M-SCF and RANKL produced by marrow stromal cells and osteoblasts are essential to promote osteoclastogenesis [2]. Osteoblasts play a key role in bone formation. They arise from MSCs and their differentiation is mainly regulated by transcription factor RUNX2 at the early time. They begin to express osteoblast phenotypic genes and synthesize the bone matrix at a later stage [7, 8]. Then osteoblasts are embedded into the bone matrix as osteocytes or die at the end of their destiny [9]. Several mechanisms including transcription factors, growth factors, hormones, and the extracellular matrix regulate these stages [7, 10]. In the last few years, significant findings have unveiled the mysterious role of the ubiquitin-dependent proteolysis system (UPS) in regulating differentiation and function of osteoclasts as well as osteoblasts [11–13].

2. Ubiquitin-Dependent Proteolysis System

Ubiquitin is a highly conserved protein which is made up of 76 amino acids. It is linked to the lysine side chains of target proteins, which results in monoubiquitination or polyubiquitination of the protein. Polyubiquitylated proteins are degraded within a cylindrical multiprotein complex that is named proteasome [14, 15], while monoubiquitination has a variety of ends except proteasomal degradation [14, 15]. For example, the adapter protein TRAF6 contains the RING finger domain which could generate nondegradative K63-linked ubiquitin and contribute to form signaling complexes [16]. This is important to mediate RANK/TRAF6 signaling [17]. To successfully add ubiquitin to target protein, three enzymes involved in this process are essential. The E1 enzyme that recruits ubiquitin is named ubiquitin-activating enzyme. The E2 enzyme, called ubiquitin-conjugating enzyme, transfers the ubiquitin to protein. The E3 enzyme, also known as ubiquitin ligase, acts as a scaffold protein which interacts with the ubiquitin-conjugating enzyme and transfers ubiquitin to protein [18]. Consequently, the UPS affects multiple processes such as protein degradation, cell death, vesicular trafficking, signal transduction, DNA repair, and stress responses [11, 14, 15, 19–23].

The ubiquitin-dependent proteolysis system plays an important role in mediating bone remodeling. Initially, by inhibiting the proteasomal function through proteasome inhibitor I (PSI), study demonstrated that the UPS is an important regulator of bone turnover and chondrogenesis [24]. And administration of proteasome inhibitor Bortezomib induced MSCs to undergo osteoblastic differentiation partially by modulation of RUNX2 in mice [25]. As a clinically available proteasome inhibitor used in myeloma, Bortezomib is also reported to promote osteoblastogenesis as well as inhibit bone resorption in clinical studies [26, 27]. Following studies demonstrated that these effects are mainly mediated by inhibiting the proteasomal degradation of important proteins, which regulate osteoblast function such as β-catenin [28] and Dkk1 [26]. Another protein stabilized by proteasome inhibitor is Gli2, which promotes bone formation through upregulating bone morphogenetic protein-2 (BMP2) [29, 30].

To date, studies investigating ubiquitin ligase and bone remodeling have demonstrated that several E3 ubiquitin ligases take part in regulation of bone metabolism. For example, the first known ubiquitin ligase affecting bone formation is Smuf1. Smurf1 has been proved to mediate RUNX2 degradation, resulting in downregulated osteoblast differentiation and bone formation [31–35]. Smurf1 also regulates the degradation of Smad1 and downregulates BMP-induced osteogenic differentiation of MSCs [35–37]. Moreover, Smuf1 mediates JunB, MEKK2, and other molecule proteasomal degradation, which causes the inhibition of osteoblast differentiation [32, 38, 39]. Another important ubiquitin ligase which regulates osteoblastogenesis is Cbl. It controls osteoblastogenesis by controlling the ubiquitination and degradation of receptor tyrosine kinases (RTKs), including IGFR, FGFR, and PDGFR [40–43]. Cbl also interacts with Pl3K to regulate bone formation [44–47]. Besides, Itch and Wwp1 are demonstrated to regulate osteogenesis by promoting RUNX2 degradation [48, 49]. On the other hand, E3 ligases also influence osteoclastogenesis and bone resorption. The E3 ligase LNX2 promotes osteoclastogenesis through M-SCF/RANKL signaling as well as the Notch pathway [13]. Another ubiquitin E3 ligase RNF146 inhibits osteoclastogenesis and cytokine production via RANK signaling [50]. As there are over 600 E3 ligases expressed in the human genome, lots of E3 ligases are found to regulate bone remodeling by governing BMU cell differentiation and function.

3. Deubiquitinases

Like other posttranslational modifications, the process of ubiquitination is reversible by the function of deubiquitinases (DUBs) which remove monoubiquitin or polyubiquitin chains from such ubiquitin-modified proteins [51]. Ubiquitin itself is a long-lived protein [52, 53]; thus, it is necessary to remove ubiquitin from proteins for maintaining a sufficient pool of free ubiquitin in the cell to sustain a normal rate of proteolysis. As key hydrolytic emzymes, DUBs hydrolyze the peptide bond that links target protein and ubiquitin [54]. Deubiquitinases are modular proteins which contain catalytic domains, ubiquitin binding domains, and protein-protein interaction domains. Such modules make positive contribution to the recognition of and binding to various chain linkages [55]. To date, about 100 DUBs have been reported to be encoded by the human genome [56, 57] (Table 1). According to their catalytic domains, these DUBs can be classified into five families including 4 thiol protease DUBS (USP, UCH, OUT, and Josephin) and 1 ubiquitin specific metalloproteases (JAMM) [54].

Deubiquitination has also been reported to be involved in many cellular functions, including DNA repair, protein degradation, cell cycle regulation, stem cell differentiation, and cell signaling [58–69]. Besides, a number of articles demonstrated that DUBs are essential for bone remodeling through regulating related BMU cell differentiation and function [69–78].

3.1. Ubiquitin-Specific Protease (USP) and the Bone

The ubiquitin-specific protease family, which contains 56 members in human, is the largest and most diverse family of the DUB families. Consisting of 6 conserved motifs, these USP catalytic domains vary between 295 and 850 residues [57]. Within these 6 motifs, there are two well-conserved motifs that are named Cys-box and His-box. They contain all the necessary catalytic residues [55, 57]. The structure of USP7 is the first well described with three subdomains resembling like a right hand [79]. The thumb and the palm contain Cys-box and His-box, respectively. The cleft between them is the catalytic center. The finger domains can interact with ubiquitin to transfer its C-terminal to the cleft [79]. Then USP5 showed us how UBL domains inserted into a single USP domain to provide additional ubiquitin binding sites which make it possible for the enzyme to bind and disassemble poly-Ub chains [80].

USP is reported to be involved in many cell functions. Most importantly, as the largest family of DUB, USPs are found to regulate bone remodeling by controlling the function of osteoblast, osteoclast, and even PTH.

3.1.1. USP and Osteoblast

USP4 is found to regulate osteoblast differentiation through the Wnt/β-catenin signaling pathway [70]. The canonical Wnt signaling pathway is essential for osteoblast differentiation and bone formation. A study demonstrates that USP4 inhibits this pathway by deubiquitinating the polyubiquitin chain from Dvl, resulting in inhibiting of Wnt signal and decreased osteoblast differentiation and mineralization [70]. USP4 also deubiquitinates other Wnt signaling components such as Nik and TCF4 [81]. There are also findings indicating that USP4 positively controls β-catenin stability by deubiquitinating, leading to the activation of Wnt signaling [82, 83]. Thus, further researches focusing on USP4 and the Wnt signaling pathway are strongly needed. Besides, USP4 is an important TGF/BMP signaling pathway regulator [69]. After phosphorylation by AKT, USP4 associates with and deubiquitinates ALK5, leading to upregulation of TGFβ signal [84]. In accordance with this finding, USP4 is also reported to interact with Smurf2 and Smad7 [85]. Furthermore, USP4 stabilizes Smad4 through inhibiting its monoubiquitination and enhances activin as well as BMP signaling [86]. Because TGF/BMP signaling plays a pivotal role in osteogenic differentiation of MSCs and bone formation [87], future studies may reveal the essential role of USP4 in control osteoblast differentiation and function through regulating this signaling.

Recently, a study has revealed that USP7 is related to osteogenic differentiation of human adipose-derived stem cells (hASCs) [71]. Like MSCs, hASC is also a stem cell with multilineage differentiation ability, including osteogenic differentiation. USP7 depletion leads to impaired osteogenic differentiation of hASCs. Overexpression of USP7 upregulates hASC osteogenesis. Moreover, knockdown of USP7 results in impaired bone formation in vivo [71]. USP7 acts to ubiquitinate and stabilize PHF8, an epigenetic factor which is essential for stem cell fate determination [88, 89]. Importantly, PHF8 triggers osteogenic differentiation of BMSCs [90]. Thus, the possible mechanism by which USP7 upregulates osteogenic differentiation of hASCs might be that USP7 stabilizes PHF8. A further study is still needed to uncover the actual mechanisms.

USP15, which is highly similar with USP4 [69], also is involved in Wnt signaling and bone formation [91]. USP15 stabilizes β-catenin and enhances Wnt signaling. These processes are initiated by FGF2, which activates MEKK2, causing recruitment of USP15 [91]. USP15 is involved in the TGF/BMP signaling pathway through connecting with ALK3, ALK5, and monoubiquitylated R-SMADs [92–94]. Future studies might reveal the relationship among USP15, TGF/BMP signaling, and osteoblast function.

Interestingly, USP9x, also known as fat facets in mouse (FAM), is closely associated with the TGF/BMP cell signaling pathway, a key signal pathway related to osteogenesis and bone formation. USP9x hydrolyzes Smad4 monoubiquitination [95–97], enhancing TGF-β signal. Moreover, USP9x interacts with the WW domain of Smurf1 and stabilizes it [72]. As told above, Smurf1 plays a pivotal role in osteogenic differentiation and bone formation [31–37]. Likely, USP11 is also involved in the TGF/BMP signaling pathway by deubiquitylating ALK5 [98]. These data suggest the potential direction of future studies.

3.1.2. USP and Osteoclast

USPs not only control osteogenic differentiation and bone formation but also regulate osteoclast differentiation and function. For example, CYLD inhibits osteoclastogenesis via downregulating RANK signaling [99]. CYLD deubiquitylates TRAF6, which transduces the RANK-mediated signal [99]. By this mechanism, CYLD inhibits osteoclast differentiation, leading to severe osteoporosis in vivo [99]. Using proteasome inhibitors, another study also emphasizes the key role of CYLD in osteoclast formation and function [100]. Furthermore, SCF-TRCP controls the degradation of CYLD itself, which pinpoints SCF-TRCP/CYLD as a pivotal modulator of osteoclastogenesis [101].

USP18 inhibits osteoclastogenesis in mice [77]. IFN signaling negatively influences osteoclastogenesis [102]. Type I IFN stimulates ISG, a ubiquitin-like protein, to express and conjugate to its target ISGylation [103]. Research data demonstrates that USP18 is a negative regulator of IFN signaling via deconjugating ISGylation [104–106]. USP18 deficiency leads to increased RANKL-mediated osteoclastogenesis, resulting in osteopenia phenotype in vivo and in vitro [77].

USP15, which regulates osteoblast function and bone formation, is connected to osteoclast function too [76]. USP15 is the key DUB which cooperates with CHMP5 to stabilize IκBα, leading to decreased RANKL-mediated NF-κB activation and osteoclast differentiation [76]. Taken together, USP15 might be an essential regulator of bone remodeling.

3.1.3. USPs and PTH

In addition to some USPs that regulate osteoblast and/or osteoclast function, there are also some other USPs which collaborate with PTH to influence bone turnover. USP2 was found to be stimulated by PTH in the bone. These osteotropic agents, including PTH, PTHrP, and PGE2, can stimulate USP2 expression selectively in the bone through the PKA/cAMP pathway [107]. A further study revealed that PTH (1-34) could upregulate the expression of USP2 and promote PTHR deubiquitination as well as stabilization [108]. Recently, research data have demonstrated that USP2 is necessary for PTH (1-34) to induce osteoblast proliferation [109]. These findings emphasize the importance of USP2 in PTH mediating anabolic action of bone formation. Another study focusing on the relationship between miRNAs and the PTH level in end-stage renal disease patients demonstrates the close connection between miR-3680-5p and the PTH level. Interestingly, the target genes of miR-3680-5p are USP2, USP6, USP46, and DLT, all of which are members of the UPS [110]. Taken together, USPs may regulate bone turnover via the influence of PTH-associated bone formation. In the future, studies about the details of this interesting mechanism will be the focus.

3.2. Ubiquitin C-Terminal Hydrolase (UCH) and Bone Formation

The members of the UCH family are several thiol proteases which contain a 230-residue domain as a catalytic core, an N-terminal, and followed by C-terminal extensions which mediate protein to protein interactions sometimes [54]. In human, four UCHs are grouped into smaller UCHs (UCH-L1 and UCH-L3) that prefer to cleave small leaving groups from the C-terminal of Ub and larger UCHs (UCH37 and BAP1) that hydrolyze polyubiquitin chains [54].

Like USPs, UCHs are also reported to have multiple functions [111–113]. Importantly, UCH-L3 deubiquitylates Smad1 and enhances osteoblast differentiation [73]. UCH-L3 physically interacts with Smad1 and stabilizes it by deubiquitylating its polyubiquitin. UCH-L3 promotes the differentiation of osteoblast from C2C12 cells, while knockdown of Uch-l3 delays osteoblast differentiation [73]. Likely, UCH37 is found to connect to Smad7 and reverse Smurf-mediated ubiquitination [114]. Moreover, UCH37 affects TGF-β signaling by connecting to ALK5 [115]. In all, UCH37 influences TGF-β signaling that suggests the role of UCH37 in regulating osteoblast differentiation and function.

3.3. Ovarian Tumor (OTU) and the Bone

The OUT family was identified based on their homology to the ovarian tumor gene [54]. In human, there are 15 OUTs that are usually grouped into three subclasses: the otubains or OTUBs, the OTUs, and the A20-like OTUs [54].

Among numerous functions of OTUs [116–120], A20 demonstrates the ability to regulate osteoclastogenesis [78, 121, 122]. Bacterial lipopolysaccharides and RANKL induce human peripheral blood mononuclear cells to express A20, which is associated with TRAF6 and NF-κB degradation. Knockdown of A20 results in increased bone resorption [121]. A20 has anti-inflammatory effects as well as antiosteoclastogenic effects [78, 122], which is mainly governed by its attenuation of NF-κB signaling through regulating IKKs [123]. Moreover, A20, which is recruited by Smad6 to TRAF6, plays an important role in inhibition of noncanonical TGF-β signaling [124], indicating its possible regulation of osteoblastogenesis via this main pathway. Besides, like A20, OTUB1 is also involved in TGF-β signaling through deubiquitination of the p-SMAD2/3 complex [125]. Studies focusing on the function of OTUs in osteoclast differentiation and function will reveal more details about the second largest DUB family.

3.4. JAB1/MPN+/MOV34 (JAMM) and the Bone

There are eight JAMM domain proteins in human, including PRPF8 without protease activity [51, 54]. All of JAMM DUBs are found with subunit complexes of proteasome, such as the proteasome 19S lid complex (POH1/hRpn11) and the COP9 signalosome (CSN5/Jab1) [54]. As an endopeptidase, RPN11 functions to cleave polyubiquitin chains from substrates [126] While CSN5/Jab1 hydrolyzes the ubiquitin-like modifier Nedd8 [127], POH1 enhances osteoclast differentiation and RANKL signaling via regulating Mitf, an important regulator of osteoclast differentiation which required gene expression [128]. MYSM1, a member of the JAMM family, is a histone DUB which specifically deubiquitinates histone 2A [129]. MYSM1 deficiency leads to decreased bone mass. MYSM1 deficiency results in impaired osteogenic differentiation of both mouse MSCs and MC3T3-E1 cell [75]. Recently, study demonstrates that MYSM1 deficiency impairs the potential for primary osteoblasts to differentiate into mature osteoblasts. Meanwhile, MYSM1 knockout reduces the proliferation of osteoclast progenitor and the osteoclast resorption activity [130]. With further studies that might uncover the detailed mechanisms of MYSM1 regulating osteoblast and osteoclast differentiation, this DUB may be a potential therapeutic target for related bone diseases.

The last member of DUBs is Josephin. There are four proteins belonging to this family, including Ataxin-3, Ataxin-3L, Josephin-1, and Josephin-2 [54]. Unfortunately, current studies have not reported the relationship between Josephin DUBs and skeleton cell differentiation and function. Further studies about the members of Josephin may find novel mechanisms by which these DUBs regulate osteoblast and osteoclast functions.

4. Perspective

The ubiquitin-dependent proteolysis system is crucial to cellular functions including skeleton cell functions. The roles of ubiquitin ligases in regulating osteoblast and osteoclast differentiation are well studied, while studies about deubiquitinating enzymes and skeleton cell differentiation are still lacking. In order to delineate the ubiquitin-dependent proteolysis system to regulate bone remodeling, it is important to establish our knowledge about DUBs and bone remodeling. To date, several DUBs are found to regulate osteoblast function (USP4, USP7, USP9x, USP15, UCH-l3, and MYSM1) and osteoclast function (CYLD, USP15, USP18, A20, and POH1) (Table 2). But the mechanisms by which these DUBs regulate skeleton cell functions are not exhaustively described. Future studies should find more DUBs that are involved in BMU cell function and bone remodeling. Importantly, the major challenge is to well describe the actual mechanisms behind these phenotypes. With these novel findings, drugs targeting these DUBs will be designed to treat related skeleton diseases.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was partly supported by grants from the National Natural Science Foundation of China (NSFC 81722014).

References

J. L. Crane, L. Xian, and X. Cao, “Role of TGF-β signaling in coupling bone remodeling,” Methods in Molecular Biology, vol. 1344, pp. 287–300, 2016.
View at: Publisher Site | Google Scholar
J. Kular, J. Tickner, S. M. Chim, and J. Xu, “An overview of the regulation of bone remodelling at the cellular level,” Clinical Biochemistry, vol. 45, no. 12, pp. 863–873, 2012.
View at: Publisher Site | Google Scholar
J. R. Edwards and G. R. Mundy, “Advances in osteoclast biology: old findings and new insights from mouse models,” Nature Reviews Rheumatology, vol. 7, no. 4, pp. 235–243, 2011.
View at: Publisher Site | Google Scholar
S. Harada and G. A. Rodan, “Control of osteoblast function and regulation of bone mass,” Nature, vol. 423, no. 6937, pp. 349–355, 2003.
View at: Publisher Site | Google Scholar
Z. Li, K. Kong, and W. Qi, “Osteoclast and its roles in calcium metabolism and bone development and remodeling,” Biochemical and Biophysical Research Communications, vol. 343, no. 2, pp. 345–350, 2006.
View at: Publisher Site | Google Scholar
N. Udagawa, N. Takahashi, T. Akatsu et al., “Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 18, pp. 7260–7264, 1990.
View at: Publisher Site | Google Scholar
P. J. Marie, “Transcription factors controlling osteoblastogenesis,” Archives of Biochemistry and Biophysics, vol. 473, no. 2, pp. 98–105, 2008.
View at: Publisher Site | Google Scholar
J. B. Lian, G. S. Stein, J. L. Stein, and A. J. van Wijnen, “Transcriptional control of osteoblast differentiation,” Biochemical Society Transactions, vol. 26, no. 1, pp. 14–21, 1998.
View at: Publisher Site | Google Scholar
S. C. Manolagas, “Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis,” Endocrine Reviews, vol. 21, no. 2, pp. 115–137, 2000.
View at: Publisher Site | Google Scholar
A. Teti, “Bone development: overview of bone cells and signaling,” Current Osteoporosis Reports, vol. 9, no. 4, pp. 264–273, 2011.
View at: Publisher Site | Google Scholar
N. Severe, F. X. Dieudonne, and P. J. Marie, “E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis,” Cell Death & Disease, vol. 4, no. 1, article e463, 2013.
View at: Publisher Site | Google Scholar
S. Strickson, C. H. Emmerich, E. T. H. Goh et al., “Roles of the TRAF6 and Pellino E3 ligases in MyD88 and RANKL signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 17, pp. E3481–E3489, 2017.
View at: Publisher Site | Google Scholar
J. Zhou, T. Fujiwara, S. Ye, X. Li, and H. Zhao, “Ubiquitin E3 ligase LNX2 is critical for osteoclastogenesis in vitro by regulating M-CSF/RANKL signaling and Notch2,” Calcified Tissue International, vol. 96, no. 5, pp. 465–475, 2015.
View at: Publisher Site | Google Scholar
A. M. Weissman, N. Shabek, and A. Ciechanover, “The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation,” Nature Reviews Molecular Cell Biology, vol. 12, no. 9, pp. 605–620, 2011.
View at: Publisher Site | Google Scholar
D. Finley, H. D. Ulrich, T. Sommer, and P. Kaiser, “The ubiquitin-proteasome system of Saccharomyces cerevisiae,” Genetics, vol. 192, no. 2, pp. 319–360, 2012.
View at: Publisher Site | Google Scholar
Z. J. Chen, “Ubiquitin signalling in the NF-κB pathway,” Nature Cell Biology, vol. 7, no. 8, pp. 758–765, 2005.
View at: Publisher Site | Google Scholar
M. C. Walsh, G. K. Kim, P. L. Maurizio, E. E. Molnar, and Y. Choi, “TRAF6 autoubiquitination-independent activation of the NFκB and MAPK pathways in response to IL-1 and RANKL,” PLoS One, vol. 3, no. 12, article e4064, 2008.
View at: Publisher Site | Google Scholar
N. Zheng and N. Shabek, “Ubiquitin ligases: structure, function, and regulation,” Annual Review of Biochemistry, vol. 86, no. 1, pp. 129–157, 2017.
View at: Publisher Site | Google Scholar
I. Gupta, K. Singh, N. K. Varshney, and S. Khan, “Delineating crosstalk mechanisms of the ubiquitin proteasome system that regulate apoptosis,” Frontiers in Cell and Development Biology, vol. 6, p. 11, 2018.
View at: Publisher Site | Google Scholar
M. M. Minor and B. L. Slagle, “Hepatitis B virus HBx protein interactions with the ubiquitin proteasome system,” Viruses, vol. 6, no. 11, pp. 4683–4702, 2014.
View at: Publisher Site | Google Scholar
A. S. Carvalho, M. S. Rodriguez, and R. Matthiesen, “Review and literature mining on proteostasis factors and cancer,” Methods in Molecular Biology, vol. 1449, pp. 71–84, 2016.
View at: Publisher Site | Google Scholar
I. Serrano, L. Campos, and S. Rivas, “Roles of E3 ubiquitin-ligases in nuclear protein homeostasis during plant stress responses,” Frontiers in Plant Science, vol. 9, p. 139, 2018.
View at: Publisher Site | Google Scholar
G. W. Zhang, H. C. Cai, and X. J. Shang, “Ubiquitin-proteasome system and sperm DNA repair: an update,” Zhonghua Nan Ke Xue, vol. 22, no. 9, pp. 834–837, 2016.
View at: Google Scholar
S. Wu and F. De Luca, “Inhibition of the proteasomal function in chondrocytes down-regulates growth plate chondrogenesis and longitudinal bone growth,” Endocrinology, vol. 147, no. 3768, pp. 3761–148, 2006.
View at: Publisher Site | Google Scholar
S. Mukherjee, N. Raje, J. A. Schoonmaker et al., “Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice,” The Journal of Clinical Investigation, vol. 118, no. 2, pp. 491–504, 2008.
View at: Publisher Site | Google Scholar
B. O. Oyajobi, I. R. Garrett, A. Gupta et al., “Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease,” British Journal of Haematology, vol. 139, no. 3, pp. 434–438, 2007.
View at: Publisher Site | Google Scholar
G. L. Uy, R. Trivedi, S. Peles et al., “Bortezomib inhibits osteoclast activity in patients with multiple myeloma,” Clinical Lymphoma & Myeloma, vol. 7, no. 9, pp. 587–9, 2007.
View at: Publisher Site | Google Scholar
Y. W. Qiang, B. Hu, Y. Chen et al., “Bortezomib induces osteoblast differentiation via Wnt-independent activation of β-catenin/TCF signaling,” Blood, vol. 113, no. 18, pp. 4319–4330, 2009.
View at: Publisher Site | Google Scholar
I. R. Garrett, D. Chen, G. Gutierrez et al., “Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro,” The Journal of Clinical Investigation, vol. 111, no. 11, pp. 1771–1782, 2003.
View at: Publisher Site | Google Scholar
M. Zhao, M. Qiao, S. E. Harris, D. Chen, B. O. Oyajobi, and G. R. Mundy, “The zinc finger transcription factor Gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling,” Molecular and Cellular Biology, vol. 26, no. 16, pp. 6197–6208, 2006.
View at: Publisher Site | Google Scholar
M. Zhao, M. Qiao, S. E. Harris, B. O. Oyajobi, G. R. Mundy, and D. Chen, “Smurf1 inhibits osteoblast differentiation and bone formation in vitro and in vivo,” The Journal of Biological Chemistry, vol. 279, no. 13, pp. 12854–12859, 2004.
View at: Publisher Site | Google Scholar
L. Zhao, J. Huang, R. Guo, Y. Wang, D. Chen, and L. Xing, “Smurf1 inhibits mesenchymal stem cell proliferation and differentiation into osteoblasts through JunB degradation,” Journal of Bone and Mineral Research, vol. 25, no. 6, pp. 1246–1256, 2010.
View at: Publisher Site | Google Scholar
R. Guo, M. Yamashita, Q. Zhang et al., “Ubiquitin ligase Smurf1 mediates tumor necrosis factor-induced systemic bone loss by promoting proteasomal degradation of bone morphogenetic signaling proteins,” The Journal of Biological Chemistry, vol. 283, no. 34, pp. 23084–23092, 2008.
View at: Publisher Site | Google Scholar
E.-J. Jeon, K.-Y. Lee, N.-S. Choi et al., “Bone morphogenetic protein-2 stimulates Runx2 acetylation,” The Journal of Biological Chemistry, vol. 281, no. 24, pp. 16502–16511, 2006.
View at: Publisher Site | Google Scholar
X. Sun, Z. Xie, Y. Ma et al., “TGF-β inhibits osteogenesis by upregulating the expression of ubiquitin ligase SMURF1 via MAPK-ERK signaling,” Journal of Cellular Physiology, vol. 233, no. 1, pp. 596–606, 2018.
View at: Publisher Site | Google Scholar
H. Zhu, P. Kavsak, S. Abdollah, J. L. Wrana, and G. H. Thomsen, “A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation,” Nature, vol. 400, no. 6745, pp. 687–693, 1999.
View at: Publisher Site | Google Scholar
G. Zhang, B. Guo, H. Wu et al., “A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy,” Nature Medicine, vol. 18, no. 2, pp. 307–314, 2012.
View at: Publisher Site | Google Scholar
M. Yamashita, S. X. Ying, G. M. Zhang et al., “Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation,” Cell, vol. 121, no. 1, pp. 101–113, 2005.
View at: Publisher Site | Google Scholar
J. Shimazu, J. Wei, and G. Karsenty, “Smurf1 inhibits osteoblast differentiation, bone formation, and glucose homeostasis through serine 148,” Cell Reports, vol. 15, no. 1, pp. 27–35, 2016.
View at: Publisher Site | Google Scholar
X. Du, Y. Xie, C. J. Xian, and L. Chen, “Role of FGFs/FGFRs in skeletal development and bone regeneration,” Journal of Cellular Physiology, vol. 227, no. 12, pp. 3731–3743, 2012.
View at: Publisher Site | Google Scholar
S. Mohan and C. Kesavan, “Role of insulin-like growth factor-1 in the regulation of skeletal growth,” Current Osteoporosis Reports, vol. 10, no. 2, pp. 178–186, 2012.
View at: Publisher Site | Google Scholar
C. Rubin, G. Gur, and Y. Yarden, “Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation,” Cell Research, vol. 15, no. 1, pp. 66–71, 2005.
View at: Publisher Site | Google Scholar
P. J. Marie, “Fibroblast growth factor signaling controlling bone formation: an update,” Gene, vol. 498, no. 1, pp. 1–4, 2012.
View at: Publisher Site | Google Scholar
N. Severe, H. Miraoui, and P. J. Marie, “The casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination,” The Journal of Biological Chemistry, vol. 286, no. 27, pp. 24443–24450, 2011.
View at: Publisher Site | Google Scholar
T. Brennan, N. S. Adapala, M. F. Barbe, V. Yingling, and A. Sanjay, “Abrogation of Cbl-PI3K interaction increases bone formation and osteoblast proliferation,” Calcified Tissue International, vol. 89, no. 5, pp. 396–410, 2011.
View at: Publisher Site | Google Scholar
V. Scanlon, B. Walia, J. Yu et al., “Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation,” Bone, vol. 95, pp. 124–135, 2017.
View at: Publisher Site | Google Scholar
V. Scanlon, D. Y. Soung, N. S. Adapala et al., “Role of Cbl-PI3K interaction during skeletal remodeling in a murine model of bone repair,” PLoS One, vol. 10, no. 9, article e0138194, 2015.
View at: Publisher Site | Google Scholar
L. Shu, H. Zhang, B. F. Boyce, and L. Xing, “Ubiquitin E3 ligase Wwp1 negatively regulates osteoblast function by inhibiting osteoblast differentiation and migration,” Journal of Bone and Mineral Research, vol. 28, no. 9, pp. 1925–1935, 2013.
View at: Publisher Site | Google Scholar
J. Liu, X. Li, H. Zhang et al., “Ubiquitin E3 ligase itch negatively regulates osteoblast function by promoting proteasome degradation of osteogenic proteins,” Bone & Joint Research, vol. 6, no. 3, pp. 154–161, 2017.
View at: Publisher Site | Google Scholar
Y. Matsumoto, J. Larose, O. A. Kent et al., “RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146,” The Journal of Clinical Investigation, vol. 127, no. 4, pp. 1303–1315, 2017.
View at: Publisher Site | Google Scholar
D. Komander, M. J. Clague, and S. Urbe, “Breaking the chains: structure and function of the deubiquitinases,” Nature Reviews. Molecular Cell Biology, vol. 10, no. 8, pp. 550–563, 2009.
View at: Publisher Site | Google Scholar
S. Swaminathan, A. Y. Amerik, and M. Hochstrasser, “The Doa4 deubiquitinating enzyme is required for ubiquitin homeostasis in yeast,” Molecular Biology of the Cell, vol. 10, no. 8, pp. 2583–2594, 1999.
View at: Publisher Site | Google Scholar
A. L. Haas and P. M. Bright, “The dynamics of ubiquitin pools within cultured human lung fibroblasts,” The Journal of Biological Chemistry, vol. 262, no. 1, pp. 345–351, 1987.
View at: Google Scholar
Z. M. Eletr and K. D. Wilkinson, “Regulation of proteolysis by human deubiquitinating enzymes,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1843, no. 1, pp. 114–128, 2014.
View at: Publisher Site | Google Scholar
F. E. Reyes-Turcu and K. D. Wilkinson, “Polyubiquitin binding and disassembly by deubiquitinating enzymes,” Chemical Reviews, vol. 109, no. 4, pp. 1495–1508, 2009.
View at: Publisher Site | Google Scholar
S. M. B. Nijman, M. P. A. Luna-Vargas, A. Velds et al., “A genomic and functional inventory of deubiquitinating enzymes,” Cell, vol. 123, no. 5, pp. 773–786, 2005.
View at: Publisher Site | Google Scholar
Y. Ye, H. Scheel, K. Hofmann, and D. Komander, “Dissection of USP catalytic domains reveals five common insertion points,” Molecular BioSystems, vol. 5, no. 12, pp. 1797–1808, 2009.
View at: Publisher Site | Google Scholar
S. K. Kwon, M. Saindane, and K. H. Baek, “p53 stability is regulated by diverse deubiquitinating enzymes,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, vol. 1868, no. 2, pp. 404–411, 2017.
View at: Publisher Site | Google Scholar
A. Spolverini, G. Fuchs, D. R. Bublik, and M. Oren, “Let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery,” Oncogene, vol. 36, no. 42, pp. 5819–5828, 2017.
View at: Publisher Site | Google Scholar
K. P. Lai, A. H. Y. Cheung, and W. K. F. Tse, “Deubiquitinase Usp18 prevents cellular apoptosis from oxidative stress in liver cells,” Cell Biology International, vol. 41, no. 8, pp. 914–921, 2017.
View at: Publisher Site | Google Scholar
A. Sobol, C. Askonas, S. Alani et al., “Deubiquitinase OTUD6B isoforms are important regulators of growth and proliferation,” Molecular Cancer Research, vol. 15, no. 2, pp. 117–127, 2017.
View at: Publisher Site | Google Scholar
H. M. Ng, L. Wei, L. Lan, and M. S. Y. Huen, “The Lys63-deubiquitylating enzyme BRCC36 limits DNA break processing and repair,” The Journal of Biological Chemistry, vol. 291, no. 31, pp. 16197–16207, 2016.
View at: Publisher Site | Google Scholar
Z. Wang, H. Zhang, J. Liu et al., “USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response,” Genes & Development, vol. 30, no. 8, pp. 946–959, 2016.
View at: Publisher Site | Google Scholar
O. M. Khan, J. Carvalho, B. Spencer-Dene et al., “The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer,” The Journal of Clinical Investigation, vol. 128, no. 4, pp. 1326–1337, 2018.
View at: Publisher Site | Google Scholar
S. Haq, B. Suresh, and S. Ramakrishna, “Deubiquitylating enzymes as cancer stem cell therapeutics,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, vol. 1869, no. 1, pp. 1–10, 2018.
View at: Publisher Site | Google Scholar
C. Lancini, P. C. M. van den Berk, J. H. A. Vissers et al., “Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells,” The Journal of Experimental Medicine, vol. 211, no. 9, pp. 1759–1777, 2014.
View at: Publisher Site | Google Scholar
J. Park, M. S. Kwon, E. E. K. Kim, H. Lee, and E. J. Song, “USP35 regulates mitotic progression by modulating the stability of Aurora B,” Nature Communications, vol. 9, no. 1, p. 688, 2018.
View at: Publisher Site | Google Scholar
B. Suresh, J. Lee, H. Kim, and S. Ramakrishna, “Regulation of pluripotency and differentiation by deubiquitinating enzymes,” Cell Death and Differentiation, vol. 23, no. 8, pp. 1257–1264, 2016.
View at: Publisher Site | Google Scholar
L. Herhaus and G. P. Sapkota, “The emerging roles of deubiquitylating enzymes (DUBs) in the TGFβ and BMP pathways,” Cellular Signalling, vol. 26, no. 10, pp. 2186–2192, 2014.
View at: Publisher Site | Google Scholar
F. Zhou, F. Li, P. Fang et al., “Ubiquitin-specific protease 4 antagonizes osteoblast differentiation through Dishevelled,” Journal of Bone and Mineral Research, vol. 31, no. 10, pp. 1888–1898, 2016.
View at: Publisher Site | Google Scholar
Y. Tang, L. Lv, W. Li et al., “Protein deubiquitinase USP7 is required for osteogenic differentiation of human adipose-derived stem cells,” Stem Cell Research & Therapy, vol. 8, no. 1, p. 186, 2017.
View at: Publisher Site | Google Scholar
Y. Xie, M. Avello, M. Schirle et al., “Deubiquitinase FAM/USP9X interacts with the E3 ubiquitin ligase SMURF1 protein and protects it from ligase activity-dependent self-degradation,” The Journal of Biological Chemistry, vol. 288, no. 5, pp. 2976–2985, 2013.
View at: Publisher Site | Google Scholar
J. Y. Kim, J. M. Lee, and J. Y. Cho, “Ubiquitin C-terminal hydrolase-L3 regulates Smad1 ubiquitination and osteoblast differentiation,” FEBS Letters, vol. 585, no. 8, pp. 1121–1126, 2011.
View at: Publisher Site | Google Scholar
F. He, D. Lu, B. Jiang et al., “X-linked intellectual disability gene CUL4B targets Jab1/CSN5 for degradation and regulates bone morphogenetic protein signaling,” Biochimica et Biophysica Acta, vol. 1832, no. 5, pp. 595–605, 2013.
View at: Publisher Site | Google Scholar
P. Li, Y. M. Yang, S. Sanchez et al., “Deubiquitinase MYSM1 is essential for normal bone formation and mesenchymal stem cell differentiation,” Scientific Reports, vol. 6, no. 1, p. 22211, 2016.
View at: Publisher Site | Google Scholar
M. B. Greenblatt, K. Park, H. Oh et al., “CHMP5 controls bone turnover rates by dampening NF-κB activity in osteoclasts,” The Journal of Experimental Medicine, vol. 212, no. 8, pp. 1283–1301, 2015.
View at: Publisher Site | Google Scholar
H. Y. Yim, C. Park, Y. D. Lee et al., “Elevated response to type I IFN enhances RANKL-mediated osteoclastogenesis in Usp18-knockout mice,” Journal of Immunology, vol. 196, no. 9, pp. 3887–3895, 2016.
View at: Publisher Site | Google Scholar
J. Y. Hong, W. J. Bae, J. K. Yi, G. T. Kim, and E. C. Kim, “Anti-inflammatory and anti-osteoclastogenic effects of zinc finger protein A20 overexpression in human periodontal ligament cells,” Journal of Periodontal Research, vol. 51, no. 4, pp. 529–539, 2016.
View at: Publisher Site | Google Scholar
M. Hu, P. Li, M. Li et al., “Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde,” Cell, vol. 111, no. 7, pp. 1041–1054, 2002.
View at: Publisher Site | Google Scholar
G. V. Avvakumov, J. R. Walker, S. Xue et al., “Two ZnF-UBP domains in isopeptidase T (USP5),” Biochemistry, vol. 51, no. 6, pp. 1188–1198, 2012.
View at: Publisher Site | Google Scholar
B. Zhao, C. Schlesiger, M. G. Masucci, and K. Lindsten, “The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway,” Journal of Cellular and Molecular Medicine, vol. 13, no. 8B, pp. 1886–1895, 2009.
View at: Publisher Site | Google Scholar
S. I. Yun, H. H. Kim, J. H. Yoon et al., “Ubiquitin specific protease 4 positively regulates the WNT/β-catenin signaling in colorectal cancer,” Molecular Oncology, vol. 9, no. 9, pp. 1834–1851, 2015.
View at: Publisher Site | Google Scholar
S. J. Hwang, H. W. Lee, H. R. Kim et al., “Ubiquitin-specific protease 4 controls metastatic potential through β-catenin stabilization in brain metastatic lung adenocarcinoma,” Scientific Reports, vol. 6, no. 1, p. 21596, 2016.
View at: Publisher Site | Google Scholar
L. Zhang, F. F. Zhou, Y. Drabsch et al., “USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor,” Nature Cell Biology, vol. 14, no. 7, pp. 717–726, 2012.
View at: Publisher Site | Google Scholar
L. Xiao, X. Peng, F. Liu et al., “AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by Smurf2 and deubiquitinating enzyme USP4,” BMC Cell Biology, vol. 16, no. 1, p. 7, 2015.
View at: Publisher Site | Google Scholar
F. Zhou, F. Xie, K. Jin et al., “USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling,” The EMBO Journal, vol. 36, no. 11, pp. 1623–1639, 2017.
View at: Publisher Site | Google Scholar
P. Garg, M. M. Mazur, A. C. Buck, M. E. Wandtke, J. Liu, and N. A. Ebraheim, “Prospective review of mesenchymal stem cells differentiation into osteoblasts,” Orthopaedic Surgery, vol. 9, no. 1, pp. 13–19, 2017.
View at: Publisher Site | Google Scholar
Q. Wang, S. Ma, N. Song et al., “Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis,” The Journal of Clinical Investigation, vol. 126, no. 6, pp. 2205–2220, 2016.
View at: Publisher Site | Google Scholar
Y. Tang, Y. Z. Hong, H. J. Bai et al., “Plant homeo domain finger protein 8 regulates mesodermal and cardiac differentiation of embryonic stem cells through mediating the histone demethylation of pmaip1,” Stem Cells, vol. 34, no. 6, pp. 1527–1540, 2016.
View at: Publisher Site | Google Scholar
Q. Han, P. Yang, Y. Wu et al., “Epigenetically modified bone marrow stromal cells in silk scaffolds promote craniofacial bone repair and wound healing,” Tissue Engineering. Part A, vol. 21, no. 15-16, pp. 2156–2165, 2015.
View at: Publisher Site | Google Scholar
M. B. Greenblatt, D. Y. Shin, H. Oh et al., “MEKK2 mediates an alternative β-catenin pathway that promotes bone formation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 9, pp. E1226–E1235, 2016.
View at: Publisher Site | Google Scholar
P. J. A. Eichhorn, L. Rodón, A. Gonzàlez-Juncà et al., “USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma,” Nature Medicine, vol. 18, no. 3, pp. 429–435, 2012.
View at: Publisher Site | Google Scholar
L. Herhaus, M. A. al-Salihi, K. S. Dingwell et al., “USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling,” Open Biology, vol. 4, no. 5, article 140065, 2014.
View at: Publisher Site | Google Scholar
M. Inui, A. Manfrin, A. Mamidi et al., “USP15 is a deubiquitylating enzyme for receptor-activated SMADs,” Nature Cell Biology, vol. 13, no. 11, pp. 1368–1375, 2011.
View at: Publisher Site | Google Scholar
M. J. Stinchfield, N. T. Takaesu, J. C. Quijano et al., “Fat facets deubiquitylation of Medea/Smad4 modulates interpretation of a Dpp morphogen gradient,” Development, vol. 139, no. 15, pp. 2721–2729, 2012.
View at: Publisher Site | Google Scholar
S. Dupont, A. Mamidi, M. Cordenonsi et al., “FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination,” Cell, vol. 136, no. 1, pp. 123–135, 2009.
View at: Publisher Site | Google Scholar
S. Stegeman, L. A. Jolly, S. Premarathne et al., “Loss of Usp9x disrupts cortical architecture, hippocampal development and TGFβ-mediated axonogenesis,” PLoS One, vol. 8, no. 7, article e68287, 2013.
View at: Publisher Site | Google Scholar
M. A. Al-Salihi, L. Herhaus, T. Macartney, and G. P. Sapkota, “USP11 augments TGFβ signalling by deubiquitylating ALK5,” Open Biology, vol. 2, no. 6, article 120063, 2012.
View at: Publisher Site | Google Scholar
W. Jin, M. Chang, E. M. Paul et al., “Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice,” The Journal of Clinical Investigation, vol. 118, no. 5, pp. 1858–1866, 2008.
View at: Publisher Site | Google Scholar
E. Ang, N. J. Pavlos, S. L. Rea et al., “Proteasome inhibitors impair RANKL-induced NF-kappaB activity in osteoclast-like cells via disruption of p62, TRAF6, CYLD, and IkappaBalpha signaling cascades,” Journal of Cellular Physiology, vol. 220, no. 2, pp. 450–459, 2009.
View at: Publisher Site | Google Scholar
X. Wu, H. Fukushima, B. J. North et al., “SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination,” Oncotarget, vol. 5, no. 12, pp. 4211–4221, 2014.
View at: Publisher Site | Google Scholar
H. Takayanagi, S. Kim, K. Matsuo et al., “RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta,” Nature, vol. 416, no. 6882, pp. 744–749, 2002.
View at: Publisher Site | Google Scholar
D. Zhang and D. E. Zhang, “Interferon-stimulated gene 15 and the protein ISGylation system,” Journal of Interferon & Cytokine Research, vol. 31, no. 1, pp. 119–130, 2011.
View at: Publisher Site | Google Scholar
A. Basters, K. P. Knobeloch, and G. Fritz, “How USP18 deals with ISG15-modified proteins: structural basis for the specificity of the protease,” The FEBS Journal, vol. 285, no. 6, pp. 1024–1029, 2018.
View at: Publisher Site | Google Scholar
J. P. Taylor, M. N. Cash, K. E. Santostefano, M. Nakanishi, N. Terada, and M. A. Wallet, “CRISPR/Cas9 knockout of USP18 enhances type I IFN responsiveness and restricts HIV-1 infection in macrophages,” Journal of Leukocyte Biology, 2018.
View at: Publisher Site | Google Scholar
P. S. Sung, S. H. Hong, J. H. Chung et al., “IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection,” Scientific Reports, vol. 7, no. 1, p. 3821, 2017.
View at: Publisher Site | Google Scholar
R. R. Miles, J. P. Sluka, D. L. Halladay et al., “Parathyroid hormone (hPTH 1-38) stimulates the expression of UBP41, an ubiquitin-specific protease, in bone,” Journal of Cellular Biochemistry, vol. 85, no. 2, pp. 229–242, 2002.
View at: Publisher Site | Google Scholar
V. Alonso, C. E. Magyar, B. Wang, A. Bisello, and P. A. Friedman, “Ubiquitination-deubiquitination balance dictates ligand-stimulated PTHR sorting,” Journal of Bone and Mineral Research, vol. 26, no. 12, pp. 2923–2934, 2011.
View at: Publisher Site | Google Scholar
J. Shirakawa, H. Harada, M. Noda, and Y. Ezura, “PTH-induced osteoblast proliferation requires upregulation of the ubiquitin-specific peptidase 2 (Usp2) expression,” Calcified Tissue International, vol. 98, no. 3, pp. 306–315, 2016.
View at: Publisher Site | Google Scholar
S. Jeong, J. M. Oh, K. H. Oh, and I. W. Kim, “Differentially expressed miR-3680-5p is associated with parathyroid hormone regulation in peritoneal dialysis patients,” PLoS One, vol. 12, no. 2, article e0170535, 2017.
View at: Publisher Site | Google Scholar
E. Kobayashi, M. Aga, S. Kondo et al., “C-terminal farnesylation of UCH-L1 plays a role in transport of Epstein-Barr virus primary oncoprotein LMP1 to exosomes,” mSphere, vol. 3, no. 1, pp. e00030–e00018, 2018.
View at: Publisher Site | Google Scholar
J. Ge, W. Hu, H. Zhou, J. Yu, C. Sun, and W. Chen, “Ubiquitin carboxyl-terminal hydrolase isozyme L5 inhibits human glioma cell migration and invasion via downregulating SNRPF,” Oncotarget, vol. 8, no. 69, pp. 113635–113649, 2017.
View at: Publisher Site | Google Scholar
H. Peng, J. Prokop, J. Karar et al., “Familial and Somatic BAP1 mutations inactivate ASXL1/2-mediated allosteric regulation of BAP1 deubiquitinase by targeting multiple independent domains,” Cancer Research, vol. 78, no. 5, pp. 1200–1213, 2018.
View at: Publisher Site | Google Scholar
S. J. Wicks, K. Haros, M. Maillard et al., “The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling,” Oncogene, vol. 24, no. 54, pp. 8080–8084, 2005.
View at: Publisher Site | Google Scholar
A. J. Cutts, S. M. Soond, S. Powell, and A. Chantry, “Early phase TGFβ receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses,” The International Journal of Biochemistry & Cell Biology, vol. 43, no. 4, pp. 604–612, 2011.
View at: Publisher Site | Google Scholar
L. Zhao, X. Wang, Y. Yu et al., “OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR,” The Journal of Biological Chemistry, vol. 293, no. 13, pp. 4883–4892, 2018.
View at: Publisher Site | Google Scholar
S. Wang, K. Wu, Q. Qian et al., “Non-canonical regulation of SPL transcription factors by a human OTUB1-like deubiquitinase defines a new plant type rice associated with higher grain yield,” Cell Research, vol. 27, no. 9, pp. 1142–1156, 2017.
View at: Publisher Site | Google Scholar
K. Kato, K. Nakajima, A. Ui, Y. Muto-Terao, H. Ogiwara, and S. Nakada, “Fine-tuning of DNA damage-dependent ubiquitination by OTUB2 supports the DNA repair pathway choice,” Molecular Cell, vol. 53, no. 4, pp. 617–630, 2014.
View at: Publisher Site | Google Scholar
A. S. Chitre, M. G. Kattah, Y. Y. Rosli et al., “A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function,” PLoS Pathogens, vol. 14, no. 3, article e1006806, 2018.
View at: Publisher Site | Google Scholar
F. Ikeda, “Linear ubiquitination signals in adaptive immune responses,” Immunological Reviews, vol. 266, no. 1, pp. 222–236, 2015.
View at: Publisher Site | Google Scholar
G. Mabilleau, D. Chappard, and A. Sabokbar, “Role of the A20-TRAF6 axis in lipopolysaccharide-mediated osteoclastogenesis,” The Journal of Biological Chemistry, vol. 286, no. 5, pp. 3242–3249, 2011.
View at: Publisher Site | Google Scholar
M. J. Lee, E. Lim, S. H. Mun et al., “Intravenous immunoglobulin (IVIG) attenuates TNF-induced pathologic bone resorption and suppresses osteoclastogenesis by inducing A20 expression,” Journal of Cellular Physiology, vol. 231, no. 2, pp. 449–458, 2016.
View at: Publisher Site | Google Scholar
N. Shembade, A. Ma, and E. W. Harhaj, “Inhibition of NF-κB signaling by A20 through disruption of ubiquitin enzyme complexes,” Science, vol. 327, no. 5969, pp. 1135–1139, 2010.
View at: Publisher Site | Google Scholar
S. M. Jung, J. H. Lee, J. Park et al., “Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6,” Nature Communications, vol. 4, no. 1, p. 2562, 2013.
View at: Publisher Site | Google Scholar
L. Herhaus, M. al-Salihi, T. Macartney, S. Weidlich, and G. P. Sapkota, “OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3,” Nature Communications, vol. 4, no. 1, p. 2519, 2013.
View at: Publisher Site | Google Scholar
S. A. H. de Poot, G. Tian, and D. Finley, “Meddling with fate: the proteasomal deubiquitinating enzymes,” Journal of Molecular Biology, vol. 429, no. 22, pp. 3525–3545, 2017.
View at: Publisher Site | Google Scholar
D. Dubiel, B. Rockel, M. Naumann, and W. Dubiel, “Diversity of COP9 signalosome structures and functional consequences,” FEBS Letters, vol. 589, no. 19, PartA, pp. 2507–2513, 2015.
View at: Publisher Site | Google Scholar
T. Schwarz, C. Sohn, B. Kaiser, E. D. Jensen, and K. C. Mansky, “The 19S proteasomal lid subunit POH1 enhances the transcriptional activation by Mitf in osteoclasts,” Journal of Cellular Biochemistry, vol. 109, no. 5, pp. 967–974, 2010.
View at: Publisher Site | Google Scholar
P. Zhu, W. Zhou, J. Wang et al., “A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation,” Molecular Cell, vol. 27, no. 4, pp. 609–621, 2007.
View at: Publisher Site | Google Scholar
M. Haffner-Luntzer, A. Kovtun, V. Fischer et al., “Loss of p53 compensates osteopenia in murine Mysm1 deficiency,” The FASEB Journal, vol. 32, no. 4, pp. 1957–1968, 2018.
View at: Publisher Site | Google Scholar

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Copyright © 2018 Yu-chen Guo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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