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Deubiquitinase

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https://www.readbyqxmd.com/read/29227477/the-deubiquitinating-enzyme-tnfaip3-mediates-inactivation-of-hepatic-ask1-and-ameliorates-nonalcoholic-steatohepatitis
#1
Peng Zhang, Pi-Xiao Wang, Ling-Ping Zhao, Xin Zhang, Yan-Xiao Ji, Xiao-Jing Zhang, Chun Fang, Yue-Xin Lu, Xia Yang, Mao-Mao Gao, Yan Zhang, Song Tian, Xue-Yong Zhu, Jun Gong, Xin-Liang Ma, Feng Li, Zhihua Wang, Zan Huang, Zhi-Gang She, Hongliang Li
Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes...
December 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29212181/insulin-like-growth-factor-2-mrna-binding-protein-3-igf2bp3-promotes-lung-tumorigenesis-via-attenuating-p53-stability
#2
Wei Zhao, Dan Lu, Liang Liu, Juan Cai, Yu Zhou, Ying Yang, Yu Zhang, Jun Zhang
Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3/IMP3/KOC), initially identified as an RNA-binding protein, is highly expressed in embryonic tissues and a variety of cancers. Previously, our group reported that IGF2BP3 may serve as a potential diagnostic marker for lung cancer. However, little is known about the function of IGF2BP3 in lung cancer development. Here we demonstrate that IGF2BP3 expression was markedly increased in lung cancer tissues compared to normal tissues at both mRNA and protein levels...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29203593/loss-of-p53-compensates-osteopenia-in-murine-mysm1-deficiency
#3
Melanie Haffner-Luntzer, Anna Kovtun, Verena Fischer, Katja Prystaz, Adelheid Hainzl, Carsten M Kroeger, Ioanna Krikki, Titus J Brinker, Anita Ignatius, Martina Gatzka
Histone modifications critically contribute to the epigenetic orchestration of bone homeostasis-in part, by modifying the access of transcription factors to specific genes involved in the osteogenic differentiation process of bone marrow mesenchymal stem cells (MSCs) and osteoblasts. Based on our previous finding that histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53 axis in hematopoiesis and tissue development, we analyzed the molecular basis of the skeletal phenotype of Mysm1-deficient mice and dissected the underlying p53-dependent and -independent mechanisms...
December 4, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29201911/transmissible-gastroenteritis-virus-papain-like-protease-1-antagonizes-production-of-interferon-%C3%AE-through-its-deubiquitinase-activity
#4
Xiaoliang Hu, Jin Tian, Hongtao Kang, Dongchun Guo, Jiasen Liu, Dafei Liu, Qian Jiang, Zhijie Li, Juanjuan Qu, Liandong Qu
Coronaviruses (CoVs), such as human coronavirus NL63 (HCoV-NL63), severe acute respiratory syndrome CoV (SARS-CoV), murine hepatitis virus (MHV), porcine epidemic diarrhea virus (PEDV), and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), encode papain-like (PL) proteases that inhibit Sendai virus- (SeV-) induced interferon (IFN-β) production. Recently, the crystal structure of transmissible gastroenteritis virus (TGEV) PL1 has been solved, which was similar to that of SARS-CoV PL2pro, which may antagonize host innate immunity...
2017: BioMed Research International
https://www.readbyqxmd.com/read/29200206/discovery-and-characterization-of-highly-potent-and-selective-allosteric-usp7-inhibitors
#5
Gerald Gavory, Colin R O'Dowd, Matthew D Helm, Jakub Flasz, Elias Arkoudis, Anthony Dossang, Caroline Hughes, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Oliver Barker, Hugues Miel, Timothy Harrison
Given the importance of ubiquitin-specific protease 7 (USP7) in oncogenic pathways, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, however, the development of validated deubiquitinase (DUB) inhibitors that exhibit drug-like properties and a well-defined mechanism of action has proven particularly challenging. In this article, we describe the identification, optimization and detailed characterization of highly potent (IC50 < 10 nM), selective USP7 inhibitors together with their less active, enantiomeric counterparts...
December 4, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29180353/clec16a-nrdp1-and-usp8-form-a-ubiquitin-dependent-tripartite-complex-that-regulates-beta-cell-mitophagy
#6
Gemma Pearson, Biaoxin Chai, Tracy Vozheiko, Xueying Liu, Malathi Kandarpa, Robert C Piper, Scott A Soleimanpour
Mitophagy is a cellular quality control pathway, which is essential to eliminate unhealthy mitochondria. While mitophagy is critical to pancreatic β-cell function, the post-translational signals governing β-cell mitochondrial turnover are unknown. Here we report that ubiquitination is essential for the assembly of a mitophagy regulatory complex, comprised of the E3 ligase Nrdp1, the deubiquitinase enzyme USP8, and Clec16a, a mediator of β-cell mitophagy with unclear function. We discover that the diabetes gene Clec16a encodes an E3 ligase, which promotes non-degradative ubiquitin conjugates to direct its mitophagy effectors and stabilize the Clec16a-Nrdp1-USP8 complex...
November 27, 2017: Diabetes
https://www.readbyqxmd.com/read/29178074/beyond-deubiquitylation-usp30-mediated-regulation-of-mitochondrial-homeostasis
#7
Jiayun Hou, Mohmmad Eldeeb, Xiangdong Wang
Mutations or sequence aberrations in the Parkin gene are among the most common causes of autosomal recessive Parkinson's disorder (PD). Parkin, a cytoplasmic E3 ubiquitin ligase, is involved in mitochondrial quality control pathways, including mitochondrial fission and mitophagy by autophagy-related genes. Parkin mediates the covalent addition of ubiquitin (Ub) chains to Lys 6, Lys 11, and Lys 63 on diverse mitochondrial-related target proteins. USP30, a mitochondrial deubiquitinase, promotes mitochondrial fusion by mediating the deubiquitination of ubiquitylated forms of mitofusins, such as Mfn1 and Mfn2...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29176319/e3-ubiquitin-ligase-rnf125-activates-interleukin-36-receptor-signaling-and-contributes-to-its-turnover
#8
Siddhartha S Saha, Gary Caviness, Guanghui Yi, Ernest L Raymond, M Lamine Mbow, C Cheng Kao
Signaling by the interleukin-36 receptor (IL-36R) is linked to inflammatory diseases such as psoriasis. However, the regulation of IL-36R signaling is poorly understood. Activation of IL-36R signaling in cultured cells results in an increased polyubiquitination of the receptor subunit, IL-1Rrp2. Treatment with deubiquitinases shows that the receptor subunit of IL-36R, IL-1Rrp2, is primarily polyubiquitinated at the K63 position, which is associated with endocytic trafficking and signal transduction. A minor amount of ubiquitination is at the K48 position that is associated with protein degradation...
November 25, 2017: Journal of Innate Immunity
https://www.readbyqxmd.com/read/29175422/targeting-cxcr7-improves-the-efficacy-of-breast-cancer-patients-with-tamoxifen-therapy
#9
REVIEW
Mingang Hao, Xiaoling Weng, Yingying Wang, Xueqin Sun, Tingting Yan, Yu Li, Lidan Hou, Xiangjun Meng, Jianhua Wang
Chemokine (C-X-C motif) receptor 7 (CXCR7) has been established to be involved in breast cancer (BCa) progression. However, the role of CXCR7 in different subtype of BCa still remains unclear. Here we note that CXCR7 expression is significantly amplified in Luminal type BCa tissues as compared with Her2 and TNBC types through data-mining in TCGA datasets, and its protein level positively correlates with ERα expression by staining of human BCa tissue. Interestingly, alteration of CXCR7 expression in Luminal type BCa cells is able to modulate the expression of ERαthrough ubiquitinationat post-translational level...
November 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29166644/cylindromatosis-cyld-a-deubiquitinase-attenuates-inflammatory-signaling-pathways-by-activating-toll-like-receptor-3-in-human-mesangial-cells
#10
Tadaatsu Imaizumi, Ryo Hayakari, Shojiro Watanabe, Tomomi Aizawa, Tomoh Matsumiya, Hidemi Yoshida, Kazushi Tsuruga, Shogo Kawaguchi, Hiroshi Tanaka
BACKGROUND/AIMS: Cylindromatosis (CYLD), a deubiquitinase, negatively regulates nuclear factor-κB in various cells. However, its potential roles in glomerular inflammation remain unclear. Because the activation of the Toll-like receptor 3 (TLR3)/type I interferon (IFN) pathways plays a pivotal role in chronic kidney diseases (CKD), we examined the role of CYLD in the TLR3 signaling in cultured human mesangial cells (MCs). METHODS: We stimulated CYLD-silenced MCs with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of dsRNA, and studied representative TLR3/IFN-β pathways (i...
November 22, 2017: Kidney & Blood Pressure Research
https://www.readbyqxmd.com/read/29166018/discovery-of-small-molecule-inhibitors-of-ubiquitin-specific-protease-7-usp7-using-integrated-nmr-and-in-silico-techniques
#11
Paola Di Lello, Richard Pastor, Jeremy M Murray, Robert A Blake, Frederick Cohen, Terry D Crawford, Joy Drobnick, Jason Drummond, Lorna Kategaya, Tracy Kleinheinz, Till Maurer, Lionel Rouge, Xianrui Zhao, Ingrid Wertz, Chudi Ndubaku, Vickie Tsui
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53 and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)-phenol compounds described by Kategaya et al.1 as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity...
November 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29164995/novel-polyubiquitin-imaging-system-polyub-fc-reveals-that-k33-linked-polyubiquitin-is-recruited-by-sqstm1-p62
#12
Yoichi Nibe, Shigeru Oshima, Masanori Kobayashi, Chiaki Maeyashiki, Yu Matsuzawa, Kana Otsubo, Hiroki Matsuda, Emi Aonuma, Yasuhiro Nemoto, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Shinichiro Nakada, Mamoru Watanabe
Ubiquitin chains are formed with 8 structurally and functionally distinct polymers. However, the functions of each polyubiquitin remain poorly understood. We developed a polyubiquitin-mediated fluorescence complementation (PolyUb-FC) assay using Kusabira Green (KG) as a split fluorescent protein. The PolyUb-FC assay has the advantage that monoubiquitination is nonfluorescent and chain-specific poly-ubiquitination can be directly visualized in living cells without using antibodies. We applied the PolyUb-FC assay to examine K33-linked polyubiquitin...
November 22, 2017: Autophagy
https://www.readbyqxmd.com/read/29162714/ablation-of-an-ovarian-tumor-family-deubiquitinase-exposes-the-underlying-regulation-governing-the-plasticity-of-cell-cycle-progression-in-toxoplasma-gondii
#13
Animesh Dhara, Rodrigo de Paula Baptista, Jessica C Kissinger, E Charles Snow, Anthony P Sinai
The Toxoplasma genome encodes the capacity for distinct architectures underlying cell cycle progression in a life cycle stage-dependent manner. Replication in intermediate hosts occurs by endodyogeny, whereas a hybrid of schizogony and endopolygeny occurs in the gut of the definitive feline host. Here, we characterize the consequence of the loss of a cell cycle-regulated ovarian tumor (OTU family) deubiquitinase, OTUD3A of Toxoplasma gondii (TgOTUD3A; TGGT1_258780), in T. gondii tachyzoites. Rather than the mutation being detrimental, mutant parasites exhibited a fitness advantage, outcompeting the wild type...
November 21, 2017: MBio
https://www.readbyqxmd.com/read/29153505/structural-basis-for-the-inhibitory-effects-of-ubistatins-in-the-ubiquitin-proteasome-pathway
#14
Mark A Nakasone, Timothy A Lewis, Olivier Walker, Anita Thakur, Wissam Mansour, Carlos A Castañeda, Jennifer L Goeckeler-Fried, Frank Parlati, Tsui-Fen Chou, Ortal Hayat, Daoning Zhang, Christina M Camara, Steven M Bonn, Urszula K Nowicka, Susan Krueger, Michael H Glickman, Jeffrey L Brodsky, Raymond J Deshaies, David Fushman
The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it...
November 15, 2017: Structure
https://www.readbyqxmd.com/read/29147007/modulating-cellular-balance-of-rps3-mono-ubiquitination-by-both-hel2-e3-ligase-and-ubp3-deubiquitinase-regulates-protein-quality-control
#15
Youjin Jung, Hag Dong Kim, Hee Woong Yang, Hye Jin Kim, Chang-Young Jang, Joon Kim
When a ribosome complex is stalled during the translation elongation process in eukaryotes, the mono-ubiquitination of Rps3 has recently been shown to be critical to ribosome quality control. We have discovered that the regulatory role of Rps3 mono-ubiquitination is controlled by a deubiquitinase. We also showed that an autophagic signal appears to be coupled to the mono-ubiquitination of Rps3p through the entrance of Ubp3p into the autophagosome in yeasts. The mono-ubiquitination of the Rps3 protein is tightly modulated by reciprocal action between the Hel2p E3 ligase and the Ubp3p deubiquitinase in yeasts and the reciprocal action between the RNF123 E3 ligase and the USP10 deubiquitinase in mammalian cells...
November 17, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29142505/targeting-deubiquitinating-enzymes-in-cancer-stem-cells
#16
REVIEW
Hu Lei, Huizhuang Shan, Yingli Wu
Cancer stem cells (CSCs) are rare but accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. Ubiquitination and deubiquitination of stemness-related proteins are essential for CSC maintenance and differentiation, even leading to execute various stem cell fate choices. Deubiquitinating enzymes (DUBs), specifically disassembling ubiquitin chains, are important to maintain the balance between ubiquitination and deubiquitination. In this review, we have focused on the DUBs regulation of stem cell fate determination...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/29138248/usp1-uaf1-deubiquitinase-complex-stabilizes-tbk1-and-enhances-antiviral-responses
#17
Zhongxia Yu, Hui Song, Mutian Jia, Jintao Zhang, Wenwen Wang, Qi Li, Lining Zhang, Wei Zhao
Optimal activation of TANK-binding kinase 1 (TBK1) is crucial for initiation of innate antiviral immunity and maintenance of immune homeostasis. Although several E3 ubiquitin ligases have been reported to regulate TBK1 activation by mediating its polyubiquitination, the functions of deubiquitinase on TBK1 activity remain largely unclear. Here, we identified a deubiquitinase complex, which is formed by ubiquitin specific peptidase 1 (USP1) and USP1-associated factor 1 (UAF1), as a viral infection-induced physiological enhancer of TBK1 expression...
November 14, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29134486/proteasome-associated-deubiquitinases-and-cancer
#18
Arjan Mofers, Paola Pellegrini, Stig Linder, Pádraig D'Arcy
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types...
November 14, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29131570/identification-and-characterisation-of-dual-inhibitors-of-the-usp25-28-deubiquitinating-enzyme-subfamily
#19
Jonathan D Wrigley, Gerald Gavory, Iain Simpson, Marian Preston, Helen Plant, Jenna Bradley, Anne U Goeppert, Ewelina Rozycka, Gareth Davies, Jarrod Walsh, Andrea Valentine, Keeva McClelland, Krzysztofa Ewa Odrzywol, Jonathan Renshaw, Joanna Boros, Jonathan Tart, Lindsey Leach, Thorsten Nowak, Richard A Ward, Timothy Harrison, David M Andrews
The Ubiquitin Proteasome System is widely postulated to be a new and important field of drug discovery for the future, with the Ubiquitin Specific Proteases (USP) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to target this so far undruggable oncogene. Here we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and whilst displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases...
November 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29130109/deubiquitinase-usp9x-promotes-cell-migration-invasion-and-inhibits-apoptosis-of-human-pancreatic-cancer
#20
Li Liu, Dan Yao, Pengbo Zhang, Weichao Ding, Xiuzhong Zhang, Chong Zhang, Shuai Gong, Yi Zhang, Jike Wang, Ting Sun, Zeqiang Ren
Ubiquitin specific peptidase 9, X-linked (USP9X), a significant regulatory protease in protein ubiquitination, has been proven to act as a proto-oncogene in several types of cancers, such as cervix, colon, breast, brain and lung cancers. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to its high invasive and metastatic abilities. Nevertheless, whether USP9X acts as a proto-oncogene or a tumor-suppressor gene in PDAC is controversial and the mechanism of metastasis remains unknown...
December 2017: Oncology Reports
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