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Ubiquitin-specific protease

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https://www.readbyqxmd.com/read/29343584/human-herpesvirus-8-interferon-regulatory-factors-1-and-3-mediate-replication-and-latency-activities-via-interactions-with-usp7-deubiquitinase
#1
Qiwang Xiang, Hyunwoo Ju, Qian Li, Szu-Chieh Mei, Daming Chen, Young Bong Choi, John Nicholas
Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs 1-4) that likely function to suppress innate immune and cellular stress responses through inhibitory interactions with various cellular proteins involved in these activities. It is notable that vIRFs 1 and 4 have been reported to interact with the deubiquitinase USP7, substrates of which include p53 and p53-targeting and destabilizing ubiquitin E3 ligase MDM2. Structural studies of vIRF-1 and vIRF-4 USP7-binding sequences in association with USP7 have been reported; both involve interactions with N-terminal domain residues of USP7, via EGPS and ASTS motifs in vIRF-1 and vIRF-4, respectively, but vIRF-4 residues also contact the catalytic site...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29343520/evidence-for-the-isg15-specific-deubiquitinase-usp18-as-an-antineoplastic-target
#2
REVIEW
Lisa Maria Mustachio, Yun Lu, Masanori Kawakami, Jason Roszik, Sarah J Freemantle, Xi Liu, Ethan Dmitrovsky
Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target...
January 17, 2018: Cancer Research
https://www.readbyqxmd.com/read/29339500/regulation-of-the-stability-of-rgf1-receptor-by-the-ubiquitin-specific-proteases-ubp12-ubp13-is-critical-for-root-meristem-maintenance
#3
Zhichao An, Yuliang Liu, Yang Ou, Jia Li, Baowen Zhang, Daye Sun, Yu Sun, Wenqiang Tang
ROOT MERISTEM GROWTH FACTOR (RGF) 1 is an important peptide hormone that regulates root growth. Upon binding to its receptor, RGFR1, RGF1 regulates the expression of two transcription factors, PLETHORA 1 and 2 (PLT1/2), to influence root meristem development. Here, we show that the ubiquitin-specific proteases UBP12 and UBP13 are positive regulators of root meristem development and that UBP13 interacts directly with RGF1 receptor (RGFR1) and its close homolog RGFR2. The ubp12,13 double-mutant root is completely insensitive to exogenous applied RGF1...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29335415/usp48-restrains-resection-by-site-specific-cleavage-of-the-brca1-ubiquitin-mark-from-h2a
#4
Michael Uckelmann, Ruth M Densham, Roy Baas, Herrie H K Winterwerp, Alexander Fish, Titia K Sixma, Joanna R Morris
BRCA1-BARD1-catalyzed ubiquitination of histone H2A is an important regulator of the DNA damage response, priming chromatin for repair by homologous recombination. However, no specific deubiquitinating enzymes (DUBs) are known to antagonize this function. Here we identify ubiquitin specific protease-48 (USP48) as a H2A DUB, specific for the C-terminal BRCA1 ubiquitination site. Detailed biochemical analysis shows that an auxiliary ubiquitin, an additional ubiquitin that itself does not get cleaved, modulates USP48 activity, which has possible implications for its regulation in vivo...
January 15, 2018: Nature Communications
https://www.readbyqxmd.com/read/29299619/intron-specificity-in-pre-mrna-splicing
#5
REVIEW
Shravan Kumar Mishra, Poonam Thakran
The occurrence of spliceosomal introns in eukaryotic genomes is highly diverse and ranges from few introns in an organism to multiple introns per gene. Introns vary with respect to their lengths, strengths of splicing signals, and position in resident genes. Higher intronic density and diversity in genetically complex organisms relies on increased efficiency and accuracy of spliceosomes for pre-mRNA splicing. Since intron diversity is critical for functions in RNA stability, regulation of gene expression and alternative splicing, RNA-binding proteins, spliceosomal regulatory factors and post-translational modifications of splicing factors ought to make the splicing process intron-specific...
January 3, 2018: Current Genetics
https://www.readbyqxmd.com/read/29285303/insulin-receptor-substrate-4-interacts-with-ubiquitin-specific-protease-18-to-activate-the-jak-stat-signaling-pathway
#6
Baihai Jiao, Xuezhen Shi, Yanzhao Chen, Haiyan Ye, Min Yao, Wenxu Hong, Shilin Li, Xiaoqiong Duan, Yujia Li, Yancui Wang, Limin Chen
Ubiquitin-specific protease 18 (USP18) as a negative regulator of the Jak/STAT signaling pathway plays an important role in the host innate immune response. USP18 has been shown to bind to the type I interferon receptor subunit 2 (IFNAR2) to down-regulate the Jak/STAT signaling. In this study, we showed that insulin receptor substrate (IRS)-4 functioned as a novel USP18-binding protein. Co-precipitation assays revealed that two regions (amino acids 335-400 and 1094-1257) of IRS4 were related to bind to the C- terminal region of USP18...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29282303/inhibition-of-the-deubiquitinase-usp14-diminishes-direct-mhc-class-i-antigen-presentation
#7
Amy L Palmer, Annemieke de Jong, Yves Leestemaker, Paul P Geurink, Ruud H Wijdeven, Huib Ovaa, Brian P Dolan
Infected or transformed cells must present peptides derived from endogenous proteins on MHC class I molecules to be recognized and targeted for elimination by Ag-specific cytotoxic T cells. In the first step of peptide generation, proteins are degraded by the proteasome. In this study, we investigated the role of the ubiquitin-specific protease 14 (Usp14), a proteasome-associated deubiquitinase, in direct Ag presentation using a ligand-stabilized model protein expressed as a self-antigen. Chemical inhibition of Usp14 diminished direct presentation of the model antigenic peptide, and the effect was especially pronounced when presentation was restricted to the defective ribosomal product (DRiP) form of the protein...
December 27, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29277914/synaptic-localization-of-the-sumoylation-regulating-protease-senp5-in-the-adult-mouse-brain
#8
Hiroki Akiyama, Kazuhiko Nakadate, Shin-Ichi Sakakibara
Covalent conjugation of small ubiquitin-like modifiers (SUMOs) or SUMOylation is a reversible post-translational modification that regulates the stability and function of target proteins. SUMOs are removed from substrate proteins by sentrin/SUMO-specific proteases (SENPs). Numerous studies have implicated SUMOylation in various physiological and pathological processes in neurons. To understand the functional roles of SUMOylation, it is necessary to determine the distribution of enzymes regulating SUMO conjugation and deconjugation; yet, the localization of SENPs has not been described in detail in intact brain tissue...
December 26, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/29274341/the-ubiquitin-specific-protease-usp36-is-a-conserved-histone-h2b-deubiquitinase
#9
Tiffany DeVine, Rosalie C Sears, Mu-Shui Dai
Histone H2b monoubiquitination plays a critical role in the regulation of gene transcription. Deregulation of H2b monoubiquitination contributes to human pathologies, such as cancer. Here we report that human USP36 is a novel H2bub1 deubiquitinase. We show that USP36 interacts with H2b and deubiquitinates H2bub1 in cells and in vitro. Overexpression of USP36 markedly reduced the levels of H2bub1 in cells. Using the p21 gene as a model, we demonstrate that depletion of USP36 increases H2bub1 at the p21 locus, primarily within its gene body...
December 20, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29273634/loss-of-the-deubiquitinase-usp36-destabilizes-the-rna-helicase-dhx33-and-causes-preimplantation-lethality-in-mice
#10
Julia M Fraile, Diana Campos-Iglesias, Francisco Rodríguez, Aurora Astudillo, Roser Vilarrasa-Blasi, Nuria Verdaguer-Dot, Miguel A Prado, Joao A Paulo, Steven P Gygi, José I Martín-Subero, José M P Freije, Carlos López-Otín
Deubiquitinases are proteases with a wide functional diversity that profoundly impact multiple biological processes. Among them, the ubiquitin-specific protease 36 (USP36) has been implicated in the regulation of nucleolar activity. However, its functional relevance in vivo has not yet been fully described. Here, we report the generation of an Usp36-deficient mouse model to examine the function of this enzyme. We show that Usp36 depletion is lethal in pre-implantation mouse embryos, where it blocks the transition from morula to blastocyst during embryonic development...
December 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29273583/chloroplast-signaling-and-quality-control
#11
REVIEW
Jean-David Rochaix, Silvia Ramundo
Although chloroplasts contain their own genetic system and are semi-autonomous cell organelles, plastid biogenesis and homeostasis are heavily dependent on the nucleo-cytosolic compartment. These two cellular compartments are closely co-ordinated through a complex signaling network comprising both anterograde and retrograde signaling chains. Developmental changes or any perturbation in the chloroplast system induced by a particular stress resulting from changes in environmental conditions such as excess light, elevated temperature, nutrient limitation, pathogen infection, give rise to specific signals...
December 21, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29249604/selectively-modulating-conformational-states-of-usp7-catalytic-domain-for-activation
#12
Ayşegül Özen, Lionel Rougé, Charlene Bashore, Brian R Hearn, Nicholas J Skelton, Erin C Dueber
Ubiquitin-specific protease 7 (USP7) deubiquitinase activity is controlled by a number of regulatory factors, including stimulation by intramolecular accessory domains. Alone, the USP7 catalytic domain (USP7cd) shows limited activity and apo USP7cd crystal structures reveal a disrupted catalytic triad. By contrast, ubiquitin-conjugated USP7cd structures demonstrate the canonical cysteine protease active-site geometry; however, the structural features of the USP7cd that stabilize the inactive conformation and the mechanism of transition between inactive and active states remain unclear...
December 1, 2017: Structure
https://www.readbyqxmd.com/read/29236775/active-site-targeted-covalent-irreversible-inhibitors-of-usp7-impair-the-functions-of-foxp3-t-regulatory-cells-by-promoting-ubiquitination-of-tip60
#13
Feng Wang, Liqing Wang, Jian Wu, Ivan Sokirniy, Phuong Nguyen, Thomas Bregnard, Joseph Weinstock, Michael Mattern, Irina Bezsonova, Wayne W Hancock, Suresh Kumar
Accumulation of Foxp3+ T-regulatory (Treg) cells in the tumor microenvironment is associated with tumor immune evasion and poor patient outcome in the case of many solid tumors. Current therapeutic strategies for blocking Treg functions are not Treg-specific, and display only modest and transient efficacy. Recent studies revealed that ubiquitin-specific protease 7 (USP7) is essential for Treg functions by stabilizing expression of Tip60 and Foxp3, which together are central to the development and maintenance of the Treg cell lineage...
2017: PloS One
https://www.readbyqxmd.com/read/29230097/the-molecular-mechanisms-of-regulation-on-usp2-s-alternative-splicing-and-the-significance-of-its-products
#14
REVIEW
Han-Qing Zhu, Feng-Hou Gao
Ubiquitin-specific protease 2 (USP2) has a regulatory function in cell growth or death and is involved in the pathogenesis of various diseases. USP2 gene can generate 7 splicing variants through alternative splicing, and 5 variants respectively as USP2-201, USP2-202, USP2-204, USP2-205, USP2-206 can encode proteins. The influence of circadian rhythm, nutrition and androgen on specific signaling molecules or cytokines can regulate the alternative splicing of USP2. Specifically, PKC activator, IL-1β, TNF-α, PDGF-BB, TGF-β1 are all regulatory factors for USP2's alternative splicing...
2017: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29229552/caspase-6-is-a-dispensable-enabler-of-adult-mammalian-axonal-degeneration
#15
V Woo, C Cheng, A Duraikannu, A Chandrasekhar, K Purdy, J A Martinez, D W Zochodne
The progress of axonal degeneration (AxD) following injury or insult impacts both recovery from axonal transection and protection of axons from diverse insults, or axonopathy. Here we provide evidence that increases in capase-6 (Casp6) expression and action contribute to the progression of AxD. The expression of Casp6 protein and mRNA in distal branches of sensory axons undergoing AxD was confirmed. We developed and utilized a new model of axonopathy in live mice by serially visualizing the viability of cutaneous axons in the ear pinna that expressed an axonal YFP transgene, in response to capasaicin-induced AxD...
December 8, 2017: Neuroscience
https://www.readbyqxmd.com/read/29205850/ots1-dependent-desumoylation-increases-tolerance-to-high-copper-levels-in-arabidopsis
#16
Erbao Zhan, Huapeng Zhou, Sha Li, Lei Liu, Tinghong Tan, Honghui Lin
The conjugation of SUMO (small ubiquitin-like modifier) to protein substrates is a reversible process (SUMOylation/deSUMOylation) that regulates plant development and stress responses. The essential metal copper (Cu) is required for normal plant growth, but excess amounts are toxic. The SUMO E3 ligase SIZ1 and SIZ1-mediated SUMOylation function in plant tolerance to excess Cu. It is unknown whether deSUMOylation also contributes to Cu tolerance in plants. Here we report that OTS1, a protease that cleaves SUMO from its substrate proteins, participates in Cu tolerance in Arabidopsis thaliana (Arabidopsis)...
December 4, 2017: Journal of Integrative Plant Biology
https://www.readbyqxmd.com/read/29200868/prognostic-and-clinicopathological-significance-of-ubiquitin-specific-protease-22-overexpression-in-cancers-evidence-from-a-meta-analysis
#17
Ning Ao, Liang Wang, Yuqin Liu
Purpose: This meta-analysis study aimed to reveal the prognostic relevance of ubiquitin-specific protease 22 (USP22) expression in patients with cancers. Methods: PubMed, Embase, and the Cochrane Library electronic databases were searched for relevant studies published up to April 2017. The prognostic value of USP22 expression was evaluated by hazard ratio with 95% confidence intervals (CIs). Relative risk (RR) with 95% CIs assessed the effects of USP22 expression on clinicopathological parameters...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29200206/discovery-and-characterization-of-highly-potent-and-selective-allosteric-usp7-inhibitors
#18
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/29198485/nodular-fasciitis-of-the-temporomandibular-joint-a-case-report
#19
I Jenkyn, A King, K A Moutasim, S Sharma
Nodular fasciitis is a relatively rare benign lesion of the soft tissue, which often presents in the fascia or deep subcutaneous tissues. It most commonly presents in the upper extremities and trunk and the head and neck region, particularly in younger patients. Its pathogenesis is poorly understood and it is predominantly thought to be a reactive lesion, although some have suggested that it may be a benign neoplasm. Advances in molecular testing and imaging have greatly assisted diagnosis. We discuss the benefits of ubiquitin-specific protease 6 (USP6) gene rearrangement testing and magnetic resonance imaging (MRI) to aid this uncommon diagnosis...
January 2018: British Journal of Oral & Maxillofacial Surgery
https://www.readbyqxmd.com/read/29166018/discovery-of-small-molecule-inhibitors-of-ubiquitin-specific-protease-7-usp7-using-integrated-nmr-and-in-silico-techniques
#20
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
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