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Deubiquitination

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https://www.readbyqxmd.com/read/28805676/inhibitors-of-deubiquitinating-enzymes-block-hiv-1-replication-and-augment-the-presentation-of-gag-derived-mhc-i-epitopes
#1
Christian Setz, Melanie Friedrich, Pia Rauch, Kirsten Fraedrich, Alina Matthaei, Maximilian Traxdorf, Ulrich Schubert
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)-the proteasome holoenzymes and a number of ubiquitin ligases-play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity...
August 12, 2017: Viruses
https://www.readbyqxmd.com/read/28801249/p53-stability-is-regulated-by-diverse-deubiquitinating-enzymes
#2
REVIEW
Seul-Ki Kwon, Madhuri Saindane, Kwang-Hyun Baek
The tumor suppressor protein p53 has a variety of roles in responses to various stress signals. In such responses, p53 activates specific transcriptional targets that control cell cycle arrest, DNA repair, angiogenesis, autophagy, metabolism, migration, aging, senescence, and apoptosis. Since p53 has been identified as the most frequently altered gene in human cancers, regulation and stabilization of its normal functions are important. Stability of p53 is regulated by the ubiquitin-proteasome pathway (UPP)...
August 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28791349/ubiquitin-specific-peptidase-4-stabilizes-interferon-regulatory-factor-protein-and-promotes-its-function-to-facilitate-interleukin-4-expression-in-t-helper-type-2-cells
#3
Zhixiang Guo, Peng Xu, Shangqing Ge, Chengxin Zhang, Xiaoyan Zheng, Jinguo Xu, Zhuang Liu, Bin Li, Shenglin Ge
We speculated that ubiquitin specific peptidase 4 (USP4) may deubiquitinate interferon regulatory factor 4 (IRF4) and affect T helper type 2 (Th2) cell function. This study aimed to validate this hypothesis. Here, the interaction between USP4 and IRF4 were analyzed by co-immunoprecipitation assay. The deubiquitin effect of USP4 on IRF4 was analyzed by the Ni-NTA pull down assay. Luciferase reporter gene constructs were used to analyze the effects of USP4, IRF4 and nuclear factor of activated T cell-2 (NFATc2) on the activation of the interleukin-4 (IL-4) promoter...
August 3, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28776570/non-canonical-regulation-of-spl-transcription-factors-by-a-human-otub1-like-deubiquitinase-defines-a-new-plant-type-rice-associated-with-higher-grain-yield
#4
Shuansuo Wang, Kun Wu, Qian Qian, Qian Liu, Qi Li, Yajun Pan, Yafeng Ye, Xueying Liu, Jing Wang, Jianqing Zhang, Shan Li, Yuejin Wu, Xiangdong Fu
Achieving increased grain productivity has long been the overriding focus of cereal breeding programs. The ideotype approach has been used to improve rice yield potential at the International Rice Research Institute and in China. However, the genetic basis of yield-related traits in rice remains unclear. Here, we show that a major quantitative trait locus, qNPT1, acts through the determination of a 'new plant type' (NPT) architecture characterized by fewer tillers, sturdier culms and larger panicles, and it encodes a deubiquitinating enzyme with homology to human OTUB1...
August 4, 2017: Cell Research
https://www.readbyqxmd.com/read/28768102/chemical-approaches-to-intervening-in-ubiquitin-specific-protease-7-usp7-function-for-oncology-and-immune-oncology-therapies
#5
Jian Wu, Suresh Kumar, Feng Wang, Hui Wang, Lijia Chen, Patrick Arsenault, Michael Mattern, Joseph Weinstock
USP7, the most widely studied among the nearly 100 deubiquitinating enzymes, supports cancer by positively affecting tumor growth and negatively affecting the patient's immune response to tumors. Great interest exists, therefore, in developing USP7 inhibitors for clinical evaluation. While the proteasome inhibitor field has enjoyed clinical success, very few clinically appropriate effectors of deubiquitinating (protease) or ubiquitinating (ligase) enzymes have appeared. The ubiquitin protease/ligase field is moving from the initial discovery of potent, selective modulators with cell proof of concept and/or in vivo activity to the optimization of these molecules to impart drug-like properties or the discovery of new inhibitor scaffolds by improved screening or rational design...
August 2, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28765927/a-decrease-in-ubiquitination-and-resulting-prolonged-life-span-of-kit-underlies-the-kit-overexpression-mediated-imatinib-resistance-of-kit-mutation-driven-canine-mast-cell-tumor-cells
#6
Masato Kobayashi, Shiori Kuroki, Sena Kurita, Ryo Miyamoto, Hiroyuki Tani, Kyoichi Tamura, Makoto Bonkobara
Overexpression of KIT is one of the mechanisms that contributes to imatinib resistance in KIT mutation-driven tumors. Here, the mechanism underlying this overexpression of KIT was investigated using an imatinib-sensitive canine mast cell tumor (MCT) line CoMS, which has an activating mutation in KIT exon 11. A KIT-overexpressing imatinib-resistant subline, rCoMS1, was generated from CoMS cells by their continuous exposure to increasing concentrations of imatinib. Neither a secondary mutation nor upregulated transcription of KIT was detected in rCoMS1 cells...
August 1, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28762656/dub3-controls-dna-damage-signalling-by-direct-deubiquitination-of-h2ax
#7
M Rocío Delgado-Díaz, Yusé Martín, Anna Berg, Raimundo Freire, Veronique A J Smits
No abstract text is available yet for this article.
August 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28761052/uchl1-hif-1-axis-mediated-antioxidant-property-of-cancer-cells-as-a-therapeutic-target-for-radiosensitization
#8
Ryota Nakashima, Yoko Goto, Sho Koyasu, Minoru Kobayashi, Akiyo Morinibu, Michio Yoshimura, Masahiro Hiraoka, Ester M Hammond, Hiroshi Harada
Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28755289/downregulation-of-usp4-promotes-activation-of-microglia-and-subsequent-neuronal-inflammation-in-rat-spinal-cord-after-injury
#9
Xingjie Jiang, Mingchen Yu, Yiqing Ou, Yong Cao, Yu Yao, Ping Cai, Feng Zhang
NF-κB is involved in the activation of microglia, which induces secondary spinal cord injury (SCI). This process involves the activation of NF-κB signaling pathway by TRAF6 through its polyubiquitination function. We know that deubiquitination of TRAF6 mediated by deubiquitinating enzyme (DUB) significantly inhibits activation of NF-κB pathway. The ubiquitin-specific protease 4 (USP4) belongs to the deubiquitinase family. Therefore, we hypothesize that USP4 is involved in the microglial activation and subsequent neuronal inflammation after SCI...
July 28, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28754552/ubiquitin-c-terminal-hydrolase-l1-is-required-for%C3%A2-regulated-protein-degradation-through-the%C3%A2-ubiquitin-proteasome-system-in-kidney
#10
Victoria Radón, Maire Czesla, Julia Reichelt, Julia Fehlert, Anna Hammel, Alva Rosendahl, Jan-Hendrik Knop, Thorsten Wiech, Ulrich O Wenzel, Marlies Sachs, Anna T Reinicke, Rolf A K Stahl, Catherine Meyer-Schwesinger
Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a major deubiquitinating enzyme of the nervous system and associated with the development of neurodegenerative diseases. We have previously shown that UCH-L1 is found in tubular and parietal cells of the kidney and is expressed de novo in injured podocytes. Since the role of UCH-L1 in the kidney is unknown we generated mice with a constitutive UCH-L1-deficiency to determine its role in renal health and disease. UCH-L1-deficient mice developed proteinuria, without gross changes in glomerular morphology...
July 26, 2017: Kidney International
https://www.readbyqxmd.com/read/28751569/cyld-deubiquitinates-nicotinamide-adenine-dinucleotide-phosphate-oxidase-4-contributing-to-adventitial-remodeling
#11
Bing Yu, Ziyi Liu, Yi Fu, Yingbao Wang, Lu Zhang, Zeyu Cai, Fang Yu, Xian Wang, Jun Zhou, Wei Kong
OBJECTIVE: Transdifferentiation of adventitial fibroblasts (AFs) into myofibroblasts plays a critical role during the vascular remodeling that occurs during atherosclerosis, restenosis, and aortic aneurysm. The ubiquitination/deubiquitination regulatory system is essential for the quality control of proteins. The involvement of ubiquitination/deubiquitination during AF transdifferentiation remains largely unknown. In this study, we determined the role of cylindromatosis (CYLD), a deubiquitinase, in the process of AF differentiation and activation in vitro and in vivo...
July 27, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28743957/ubiquitin-specific-protease-21-stabilizes-brca2-to-control-dna-repair-and-tumor-growth
#12
Jinping Liu, Alex Kruswick, Hien Dang, Andy D Tran, So Mee Kwon, Xin Wei Wang, Philipp Oberdoerffer
Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival...
July 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28724765/translesion-polymerase-pol-%C3%AE-is-required-for-efficient-epstein-barr-virus-infectivity-and-is-regulated-by-the-viral-deubiquitinating-enzyme-bplf1
#13
Ossie F Dyson, Joseph S Pagano, Christopher B Whitehurst
Epstein-Barr Virus (EBV) infection and lytic replication are known to induce a cellular DNA damage response. Previously we showed that the virally encoded BPLF1 protein interacts with and regulates several members of the translesion synthesis pathway (TLS), a DNA damage tolerance pathway, and that these cellular factors enhance viral infectivity. BPLF1 is a late lytic cycle gene, but the protein is also packaged in the viral tegument indicating that BPLF1 may function both early and late during infection. BPLF1 expresses deubiquitinating activity that is strictly conserved across the Herpesviridae; mutation of the active-site cysteine results in loss of enzymatic activity...
July 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28722507/polyglutamine-tracts-regulate-autophagy
#14
Avraham Ashkenazi, Carla F Bento, Thomas Ricketts, Mariella Vicinanza, Farah Siddiqi, Mariana Pavel, Ferdinando Squitieri, Maarten C Hardenberg, Sara Imarisio, Fiona M Menzies, David C Rubinsztein
Expansions of polyglutamine (polyQ) tracts in different proteins cause 9 neurodegenerative conditions, such as Huntington disease and various ataxias. However, many normal mammalian proteins contain shorter polyQ tracts. As these are frequently conserved in multiple species, it is likely that some of these polyQ tracts have important but unknown biological functions. Here we review our recent study showing that the polyQ domain of the deubiquitinase ATXN3/ataxin-3 enables its interaction with BECN1/beclin 1, a key macroautophagy/autophagy initiator...
July 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28720576/deubiquitinating-enzyme-usp9x-suppresses-tumor-growth-via-lats-kinase-and-core-components-of-the-hippo-pathway
#15
Aleksandra Toloczko, Fusheng Guo, Hiu-Fung Yuen, Qing Wen, Stephen Andrew Wood, Yan Shan Ong, Pei Yi Chan, Asfa Alli Shaik, Jayantha Gunaratne, Mark John Dunne, Wanjin Hong, Siew Wee Chan
The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis...
July 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28718215/usp18-protects-against-hepatic-steatosis-and-insulin-resistance-via-its-dub-activity
#16
Shimin An, Ling-Ping Zhao, Li-Jun Shen, Siyuan Wang, Kuo Zhang, Yu Qi, Jilin Zheng, Xiao-Jing Zhang, Xue-Yong Zhu, Rong Bao, Ling Yang, Yue-Xin Lu, Zhi-Gang She, Yi-Da Tang
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we first report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating (DUB) enzyme family, plays regulatory roles in NAFLD progression. The expression of USP18 was down-regulated in the livers of non-alcoholic steatohepatitis (NASH) patients and high-fat diet (HFD) induced or genetically obese mice...
July 17, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28703681/activation-of-gene-expression-by-histone-deubiquitinase-otld1
#17
Ido Keren, Vitaly Citovsky
One of the main mechanisms of epigenetic control is post translational modification of histones, and one of the relatively less characterized, yet functionally important histone modifications is monoubiquitylation, which is reversed by histone deubiquitinases. In Arabidopsis, only two of such enzymes are known to date. One of them, OTLD1, deubiquitylates histone 2B and functions as a transcriptional repressor. But, could the same deubiquitinase act both as a repressor and an activator? Here, we addressed this question...
July 13, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28701375/spata2-regulates-the-activation-of-ripk1-by-modulating-linear-ubiquitination
#18
Ran Wei, Lily Wen Xu, Jianping Liu, Yanxia Li, Pei Zhang, Bing Shan, Xiaojuan Lu, Lihui Qian, Zheming Wu, Kangyun Dong, Hong Zhu, Lifeng Pan, Junying Yuan, Heling Pan
Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis)...
June 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28695315/ubiquitin-specific-proteases-function-in-plant-development-and-stress-responses
#19
REVIEW
Huapeng Zhou, Jinfeng Zhao, Jingqing Cai, Suyash B Patil
UBIQUITIN-SPECIFIC PROTEASES play important roles in plant development and stress responses. Protein ubiquitination and deubiquitination are reversible processes, which can modulate the stability, activity as well as subcellular localization of the substrate proteins. UBIQUITIN-SPECIFIC PROTEASE (UBP) protein family participates in protein deubiquitination. Members of UBP family are involved in a variety of physiological processes in plants, as evidenced by their functional characterization in model plant Arabidopsis and other plants...
August 2017: Plant Molecular Biology
https://www.readbyqxmd.com/read/28681694/uchl5-expression-associates-with-improved-survival-in-lymph-node-positive-rectal-cancer
#20
Leena Arpalahti, Jaana Hagström, Harri Mustonen, Mikael Lundin, Caj Haglund, Carina I Holmberg
Colorectal cancer is among the three most common cancer types for both genders, with a rising global incidence. To date, prognostic evaluation is difficult and largely dependent on early detection and successful surgery. UCHL5/Uch37 is an integral part of the protein homeostasis network as one of the three deubiquitinating enzymes associated with the 26S proteasome. Here, we have investigated in colorectal cancer the possible association of UCHL5 tumor expression and patient survival. UCHL5 tumor expression was evaluated by immunohistochemistry in 779 surgically treated colorectal cancer patients from Helsinki University Hospital, Finland, with assessment of clinicopathological parameters and the effect of UCHL5 expression on patient survival...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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