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Deubiquitinase

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https://www.readbyqxmd.com/read/29050293/proapoptotic-function-of-deubiquitinase-dusp31-in-drosophila
#1
Sergey A Sinenko
Drosophila have been used to identify new components in apoptosis regulation. The Drosophila protein Dark forms an octameric apoptosome complex that induces the initiator caspase Dronc to trigger the caspase cell death pathway and, therefore, plays an important role in controlling apoptosis. Caspases and Dark are constantly expressed in cells, but their activity is blocked by DIAP1 E3 ligase-mediated ubiquitination and subsequent inactivation or proteasomal degradation. One of the regulatory mechanisms that stabilize proapoptotic factors is the removal of ubiquitin chains by deubiquitinases...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29045389/molecular-basis-of-usp7-inhibition-by-selective-small-molecule-inhibitors
#2
Andrew P Turnbull, Stephanos Ioannidis, Wojciech W Krajewski, Adan Pinto-Fernandez, Claire Heride, Agnes C L Martin, Louise M Tonkin, Elizabeth C Townsend, Shane M Buker, David R Lancia, Justin A Caravella, Angela V Toms, Thomas M Charlton, Johanna Lahdenranta, Erik Wilker, Bruce C Follows, Nicola J Evans, Lucy Stead, Cristina Alli, Vladislav V Zarayskiy, Adam C Talbot, Alexandre J Buckmelter, Minghua Wang, Crystal L McKinnon, Fabienne Saab, Joanna F McGouran, Hannah Century, Malte Gersch, Marc S Pittman, C Gary Marshall, Tony M Raynham, Mary Simcox, Lorna M D Stewart, Sheila B McLoughlin, Jaime A Escobedo, Kenneth W Bair, Christopher J Dinsmore, Tim R Hammonds, Sunkyu Kim, Sylvie Urbé, Michael J Clague, Benedikt M Kessler, David Komander
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29045385/usp7-small-molecule-inhibitors-interfere-with-ubiquitin-binding
#3
Lorna Kategaya, Paola Di Lello, Lionel Rougé, Richard Pastor, Kevin R Clark, Jason Drummond, Tracy Kleinheinz, Eva Lin, John-Paul Upton, Sumit Prakash, Johanna Heideker, Mark McCleland, Maria Stella Ritorto, Dario R Alessi, Matthias Trost, Travis W Bainbridge, Michael C M Kwok, Taylur P Ma, Zachary Stiffler, Bradley Brasher, Yinyan Tang, Priyadarshini Jaishankar, Brian R Hearn, Adam R Renslo, Michelle R Arkin, Frederick Cohen, Kebing Yu, Frank Peale, Florian Gnad, Matthew T Chang, Christiaan Klijn, Elizabeth Blackwood, Scott E Martin, William F Forrest, James A Ernst, Chudi Ndubaku, Xiaojing Wang, Maureen H Beresini, Vickie Tsui, Carsten Schwerdtfeger, Robert A Blake, Jeremy Murray, Till Maurer, Ingrid E Wertz
The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival...
October 18, 2017: Nature
https://www.readbyqxmd.com/read/29043433/mcpip1-inhibits-coxsackievirus-b3-replication-by-targeting-viral-rna-and-negatively-regulates-virus-induced-inflammation
#4
Min Li, Kepeng Yan, Lin Wei, Yang Yang, Qian Qian, Wei Xu
Monocyte chemotactic protein-induced protein 1(MCPIP1) is identified as an important inflammatory regulator during immune response. MCPIP1 possesses antiviral activities against several viruses, such as Japanese encephalitis. However, its role on Coxsackievirus B3 (CVB3) infection, a positive-stranded RNA virus, has not been addressed. Here, we reported that MCPIP1 was up-regulated in cardiomyocytes by CVB3 infection and in hearts and pancreas of infected mice. Then we found that overexpression of MCPIP1 inhibited CVB3 replication and knockdown of it promoted virus replication...
October 17, 2017: Medical Microbiology and Immunology
https://www.readbyqxmd.com/read/29040458/orchestration-of-the-mammalian-host-cell-glucose-transporter-proteins-1-and-3-by-chlamydia-contributes-to-intracellular-growth-and-infectivity
#5
Xiaogang Wang, Kevin Hybiske, Richard S Stephens
Chlamydia are gram-negative obligate intracellular bacteria that replicate within a discrete cellular vacuole, called an inclusion. Although it is known that Chlamydia require essential nutrients from host cells to support their intracellular growth, the molecular mechanisms for acquiring these macromolecules remain uncharacterized. In the present study it was found that the expression of mammalian cell glucose transporter proteins 1 (GLUT1) and 3 (GLUT3) were up-regulated during chlamydial infection. Up-regulation was dependent on bacterial protein synthesis and Chlamydia-induced MAPK kinase activation...
October 9, 2017: Pathogens and Disease
https://www.readbyqxmd.com/read/29039082/metal-based-proteasomal-deubiquitinase-inhibitors-as-potential-anticancer-agents
#6
Xin Chen, Qianqian Yang, Lu Xiao, Daolin Tang, Q Ping Dou, Jinbao Liu
Deubiquitinases (DUBs) play an important role in protein quality control in eukaryotic cells due to their ability to specifically remove ubiquitin from substrate proteins. Therefore, recent findings have focused on the relevance of DUBs to cancer development, and pharmacological intervention on these enzymes has become a promising strategy for cancer therapy. In particular, several DUBs are physically and/or functionally associated with the proteasome and are attractive targets for the development of novel anticancer drugs...
October 16, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29029872/inhibition-of-deubiquitinases-alters-gamete-ubiquitination-states-and-sperm-oocyte-binding-ability-in-pigs
#7
Yang Wang, Lili Zhuang, Xuan Chen, Man Xu, Zuochen Li, Yi Jin
This study was undertaken to investigate the dynamics of protein ubiquitination in pig gametes and their micro-environments, as well as to explore the action of deubiquitinases (DUBs) in sperm-oocyte binding. Protein ubiquitination states were evaluated by in the ejaculated sperm, seminal plasma, epididymal sperm, oocytes, zona pellucida (ZP) and follicular fluid (FF) by western blotting. Different concentrations of PR-619, a non-selective inhibitor of DUBs, were used to treat oocytes during in vitro maturation (IVM), the maturation rate, amount of ubiquitinated ZP proteins, and ZP solubility were assessed...
October 7, 2017: Animal Reproduction Science
https://www.readbyqxmd.com/read/29029505/the-deubiquitinating-enzyme-usp5-promotes-pancreatic-cancer-via-modulating-cell-cycle-regulators
#8
Brajesh P Kaistha, Anja Krattenmacher, Johannes Fredebohm, Harald Schmidt, Diana Behrens, Miriam Widder, Thilo Hackert, Oliver Strobel, Jörg D Hoheisel, Thomas M Gress, Malte Buchholz
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. With an overall five-year survival rate remaining below 6%, there is an explicit need to search for new molecular targets for therapeutic interventions. We undertook a barcode labelled short-hairpin (shRNA) library screen in pancreatic cancer cells in order to identify novel genes promoting cancer survival and progression. Among the candidate genes identified in this screen was the deubiquitinase USP5, which subsequent gene expression analyses demonstrated to be significantly upregulated in primary human pancreatic cancer tissues...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28992318/the-deubiquitinase-uchl5-uch37-positively-regulates-hedgehog-signaling-by-deubiquitinating-smoothened
#9
Zizhang Zhou, Xia Yao, Shu Pang, Ping Chen, Weirong Jiang, Zhaoliang Shan, Qing Zhang
The Hedgehog (Hh) signaling pathway plays important roles in developmental processes including pattern formation and tissue homeostasis. The seven-pass transmembrane receptor Smoothened (Smo) is the pivotal transducer in the pathway; it, and thus the pathway overall, is regulated by ubiquitin-mediated degradation, which occurs in the absence of Hh. In the presence of Hh, the ubiquitination levels of Smo are decreased, but the molecular basis for this outcome is not well understood. Here, we identify the deubiquitinase UCHL5 as a positive regulator of the Hh pathway...
August 23, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28981114/essential-role-of-hcmv-deubiquitinase-in-promoting-oncogenesis-by-targeting-anti-viral-innate-immune-signaling-pathways
#10
Puja Kumari, Irene Saha, Athira Narayanan, Sathish Narayanan, Akinori Takaoka, Nachimuthu Senthil Kumar, Prafullakumar Tailor, Himanshu Kumar
Cancer is a multifactorial disease and virus-mediated carcinogenesis is one of the crucial factors, which is poorly understood. Human cytomegalovirus (HCMV) is a herpesvirus and its components have been evidenced to be associated with cancer of different tissue origin. However, its role in cancer remains unknown. Here, we identified a conserved herpesviral tegument protein known as pUL48 of HCMV, encoding deubiquitinase enzyme, as having a key role in carcinogenesis. We show using deubiquitinase sufficient- and deficient-HCMV that HCMV deubiquitinase is a key in inducing enhanced cellular metabolic activity through upregulation of several anti-apoptotic genes and downregulation of several pro-apoptotic genes expression...
October 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28978033/mysm1-2a-dub-is-an-epigenetic-regulator-in-human-melanoma-and-contributes-to-tumor-cell-growth
#11
Christina Wilms, Carsten M Kroeger, Adelheid V Hainzl, Ishani Banik, Clara Bruno, Ioanna Krikki, Vida Farsam, Meinhard Wlaschek, Martina V Gatzka
Histone modifying enzymes, such as histone deacetylases (HDACs) and polycomb repressive complex (PRC) components, have been implicated in regulating tumor growth, epithelial-mesenchymal transition, tumor stem cell maintenance, or repression of tumor suppressor genes - and may be promising targets for combination therapies of melanoma and other cancers. According to recent findings, the histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53-axis in hematopoiesis and tissue differentiation in mice, in part by modulating DNA-damage responses in stem cell and progenitor compartments...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28973854/proteasome-independent-polyubiquitin-linkage-regulates-synapse-scaffolding-efficacy-and-plasticity
#12
Qi Ma, Hongyu Ruan, Lisheng Peng, Mingjie Zhang, Michaela U Gack, Wei-Dong Yao
Ubiquitination-directed proteasomal degradation of synaptic proteins, presumably mediated by lysine 48 (K48) of ubiquitin, is a key mechanism in synapse and neural circuit remodeling. However, more than half of polyubiquitin (polyUb) species in the mammalian brain are estimated to be non-K48; among them, the most abundant is Lys 63 (K63)-linked polyUb chains that do not tag substrates for degradation but rather modify their properties and activity. Virtually nothing is known about the role of these nonproteolytic polyUb chains at the synapse...
September 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28968984/a-novel-deubiquitinase-inhibitor-b-ap15-triggers-apoptosis-in-both-androgen-receptor-dependent-and-independent-prostate-cancers
#13
Jianyu Cai, Xiaohong Xia, Yuning Liao, Ningning Liu, Zhiqiang Guo, Jinghong Chen, Li Yang, Huidan Long, Qianqian Yang, Xiaolan Zhang, Lu Xiao, Xuejun Wang, Hongbiao Huang, Jinbao Liu
Prostate cancer (PCa) remains a leading cause of cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrate-resistant prostate cancer (CRPC) which is currently incurable. Deubiquitinases (DUBs) associated with the 19S proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S proteasome, resulting in cell growth inhibition and apoptosis in several human cancer cell lines...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28945249/mechanism-and-regulation-of-the-lys6-selective-deubiquitinase-usp30
#14
Malte Gersch, Christina Gladkova, Alexander F Schubert, Martin A Michel, Sarah Maslen, David Komander
Damaged mitochondria undergo mitophagy, a specialized form of autophagy that is initiated by the protein kinase PINK1 and the ubiquitin E3 ligase Parkin. Ubiquitin-specific protease USP30 antagonizes Parkin-mediated ubiquitination events on mitochondria and is a key negative regulator of mitophagy. Parkin and USP30 both show a preference for assembly or disassembly, respectively, of Lys6-linked polyubiquitin, a chain type that has not been well studied. Here we report crystal structures of human USP30 bound to monoubiquitin and Lys6-linked diubiquitin, which explain how USP30 achieves Lys6-linkage preference through unique ubiquitin binding interfaces...
September 25, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28945247/structural-basis-for-specific-cleavage-of-lys6-linked-polyubiquitin-chains-by-usp30
#15
Yusuke Sato, Kei Okatsu, Yasushi Saeki, Koji Yamano, Noriyuki Matsuda, Ai Kaiho, Atsushi Yamagata, Sakurako Goto-Ito, Minoru Ishikawa, Yuichi Hashimoto, Keiji Tanaka, Shuya Fukai
Parkin ubiquitin (Ub) ligase (also known as PARK2) ubiquitinates damaged mitochondria for their clearance and quality control. USP30 deubiquitinase opposes parkin-mediated Ub-chain formation on mitochondria by preferentially cleaving Lys6-linked Ub chains. Here, we report the crystal structure of zebrafish USP30 in complex with a Lys6-linked diubiquitin (diUb or Ub2) at 1.87-Å resolution. The distal Ub-recognition mechanism of USP30 is similar to those of other USP family members, whereas Phe4 and Thr12 of the proximal Ub are recognized by a USP30-specific surface...
September 25, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28939772/interaction-between-the-aaa-atpase-p97-and-its-cofactor-ataxin3-in-health-and-disease-nucleotide-induced-conformational-changes-regulate-cofactor-binding
#16
Maya V Rao, Dewight R Williams, Simon Cocklin, Patrick J Loll
p97 is an essential ATPase associated with various cellular activities (AAA+) that functions as a segregase in diverse cellular processes, including the maintenance of proteostasis. p97 interacts with different cofactors that target it to distinct pathways; an important example is the deubiquitinase ataxin3, which collaborates with p97 in endoplasmic reticulum associated degradation (ERAD). However, the molecular details of this interaction have been unclear. Here, we characterized the binding of ataxin3 to p97, showing that ataxin3 binds with low-micromolar affinity to both wild-type p97 and mutants linked to degenerative disorders known as multisystem proteinopathy 1 (MSP1); we further showed that the stoichiometry of binding is one ataxin3 molecule per p97 hexamer...
September 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28933784/inhibition-of-the-deubiquitinase-usp5-leads-to-c-maf-protein-degradation-and-myeloma-cell-apoptosis
#17
Siyu Wang, Jiaxiang Juan, Zubin Zhang, Yanyun Du, Yujia Xu, Jiefei Tong, Biyin Cao, Michael F Moran, Yuanying Zeng, Xinliang Mao
The deubiquitinase USP5 stabilizes c-Maf, a key transcription factor in multiple myeloma (MM), but the mechanisms and significance are unclear. In the present study, USP5 was found to interact with c-Maf and prevented it from degradation by decreasing its polyubiquitination level. Specifically, the 308th and 347th lysine residues in c-Maf were critical for USP5-mediated deubiquitination and stability. There are five key domains in the USP5 protein and subsequent studies revealed that the cryptic ZnF domain and the C-box domain interacted with c-Maf but the UBA1/UBA2 domain partly increased its stability...
September 21, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28931677/structurally-guided-removal-of-deisgylase-biochemical-activity-from-papain-like-protease-originating-from-the-middle-east-respiratory-syndrome-virus
#18
Courtney M Daczkowski, Octavia Goodwin, John V Dzimianski, Jonathan J Farhat, Scott D Pegan
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen that is the causative agent for Middle East respiratory syndrome (MERS). With MERS outbreaks resulting in over 35% fatalities and now spread to 27 countries, MERS-CoV poses a significant on-going threat to global human health. As part of its viral genome, MERS-CoV encodes for a papain-like protease (PLpro) that has been observed to act as a deubiquitinase and deISGylase to antagonize IFN-I immune pathways. This activity is in addition to its viral polypeptide cleavage function...
September 20, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28919039/a-linear-diubiquitin-based-probe-for-efficient-and-selective-detection-of-the-deubiquitinating-enzyme-otulin
#19
Aurelia Weber, Paul R Elliott, Adan Pinto-Fernandez, Sarah Bonham, Benedikt M Kessler, David Komander, Farid El Oualid, Daniel Krappmann
The methionine 1 (M1)-specific deubiquitinase (DUB) OTULIN acts as a negative regulator of nuclear factor κB signaling and immune homeostasis. By replacing Gly76 in distal ubiquitin (Ub) by dehydroalanine we designed the diubiquitin (diUb) activity-based probe UbG76Dha-Ub (OTULIN activity-based probe [ABP]) that couples to the catalytic site of OTULIN and thereby captures OTULIN in its active conformation. The OTULIN ABP displays high selectivity for OTULIN and does not label other M1-cleaving DUBs, including CYLD...
October 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28900035/prion-protein-is-required-for-tumor-necrosis-factor-alpha-tnf%C3%AE-triggered-nuclear-factor-kappa-b-nf-%C3%AE%C2%BAb-signaling-and-cytokine-production
#20
Gui-Ru Wu, Tian-Chen Mu, Zhen-Xing Gao, Jun Wang, Man-Sun Sy, Chao-yang Li
The expression of normal cellular prion protein (PrP) is required for the pathogenesis of prion diseases. However, the physiological functions of PrP remain ambiguous. Here, we identified PrP as being critical for tumor necrosis factor (TNF)α-triggered signaling in a human melanoma cell line, M2, and a pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNFα upregulates the expression of p-I-kappa-B-kinase α/β (p-IKKα/β), p-p65, and p-JNK, but downregulates the IκBα protein, all of which are downstream signaling intermediates in the TNF receptor signaling cascade...
September 12, 2017: Journal of Biological Chemistry
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