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Deubiquitinase

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https://www.readbyqxmd.com/read/28098164/uncovering-the-sumoylation-and-ubiquitylation-crosstalk-in-human-cells-using-sequential-peptide-immunopurification
#1
Frédéric Lamoliatte, Francis P McManus, Ghizlane Maarifi, Mounira K Chelbi-Alix, Pierre Thibault
Crosstalk between the SUMO and ubiquitin pathways has recently been reported. However, no approach currently exists to determine the interrelationship between these modifications. Here, we report an optimized immunoaffinity method that permits the study of both protein ubiquitylation and SUMOylation from a single sample. This method enables the unprecedented identification of 10,388 SUMO sites in HEK293 cells. The sequential use of SUMO and ubiquitin remnant immunoaffinity purification facilitates the dynamic profiling of SUMOylated and ubiquitylated proteins in HEK293 cells treated with the proteasome inhibitor MG132...
January 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28096485/murine-cytomegalovirus-deubiquitinase-regulates-viral-chemokine-levels-to-control-inflammation-and-pathogenesis
#2
Adam T Hilterbrand, Daniel R Boutz, Edward M Marcotte, Jason W Upton
: Maintaining control over inflammatory processes represents a paradox for viral pathogens. Although many viruses induce host inflammatory responses to facilitate infection, control is necessary to avoid overactivation. One way is through the manipulation of proinflammatory chemokine levels, both host and viral. Murine cytomegalovirus (MCMV), a model betaherpesvirus, encodes a viral C-C chemokine, MCK2, which promotes host inflammatory responses and incorporates into virions to facilitate viral dissemination...
January 17, 2017: MBio
https://www.readbyqxmd.com/read/28091961/-1-h-13-c-and-15-n-backbone-and-side-chain-resonance-assignments-of-the-znf-ubp-domain-of-usp20-vdu2
#3
Yuanyuan Yang, Yi Wen, Naixia Zhang
Deubiquitinase USP20/VDU2 has been identified as a regulator of multiple proteins including hypoxia-inducible factor (HIF)-1α, β2-adrenergic receptor, and tumor necrosis factor receptor associated factor 6 etc. It contains four structural domains, including an N-terminal zinc-finger ubiquitin binding domain (ZnF-UBP) that potentially helps USP20 to recruit its ubiquitin substrates. Here we report the (1)H, (13)C and (15)N backbone and side-chain resonance assignments of the ZnF-UBP domain of USP20/VDU2. The BMRB accession number is 26901...
January 13, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28074857/deubiquitylation-of-hepatitis-b-virus-x-protein-hbx-by-ubiquitin-specific-peptidase-15-usp15-increases-hbx-stability-and-its-transactivation-activity
#4
Zhi-Jun Su, Jia-Shou Cao, Yan-Fang Wu, Wan-Nan Chen, Xinjian Lin, Yun-Li Wu, Xu Lin
Hepatitis B virus X protein (HBx) plays important roles in viral replication and the development of hepatocellular carcinoma. HBx is a rapid turnover protein and ubiquitin-proteasome pathway has been suggested to influence HBx stability as treatment with proteasome inhibitors increases the levels of HBx protein and causes accumulation of the polyubiquitinated forms of HBx. Deubiquitinases (DUBs) are known to act by removing ubiquitin moieties from proteins and thereby reverse their stability and/or activity...
January 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28067227/cdk4-6-dependent-activation-of-dub3-regulates-cancer-metastasis-through-snail1
#5
Tongzheng Liu, Jia Yu, Min Deng, Yujiao Yin, Haoxing Zhang, Kuntian Luo, Bo Qin, Yunhui Li, Chenming Wu, Tao Ren, Yang Han, Peng Yin, JungJin Kim, SeungBaek Lee, Jing Lin, Lizhi Zhang, Jun Zhang, Somaira Nowsheen, Liewei Wang, Judy Boughey, Matthew P Goetz, Jian Yuan, Zhenkun Lou
Tumour metastasis, the spread of cancer cells from the original tumour site followed by growth of secondary tumours at distant organs, is the primary cause of cancer-related deaths and remains poorly understood. Here we demonstrate that inhibition of CDK4/6 blocks breast tumour metastasis in the triple-negative breast cancer model, without affecting tumour growth. Mechanistically, we identify a deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a key factor promoting epithelial-mesenchymal transition and breast cancer metastasis...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28066899/a-role-for-the-histone-h2a-deubiquitinase-mysm1-in-maintenance-of-cd8-t-cells
#6
Michael Förster, Rupinder K Boora, Jessica C Petrov, Nassima Fodil, Isabella Albanese, Jamie Kim, Philippe Gros, Anastasia Nijnik
Several previous studies outlined the importance of the histone H2A deubiquitinase (H2A-DUB) MYSM1 in the regulation of stem cell quiescence and hematopoiesis. In this study we investigated the role of MYSM1 in T cell development. Using mouse models that allow conditional Mysm1 ablation at late stages of thymic development, we found that MYSM1 is intricately involved in the maintenance, activation, and survival of CD8+ T cells. Mysm1 ablation resulted in a 2-fold reduction in CD8+ T cell numbers, and also led to a hyperactivated CD8+ T cell state accompanied by impaired proliferation and increased proinflammatory cytokine production after ex vivo stimulation...
January 9, 2017: Immunology
https://www.readbyqxmd.com/read/28063927/deubiquitinase-usp12-promotes-lps-induced-macrophage-responses-through-inhibition-of-i%C3%AE%C2%BAb%C3%AE
#7
Tapan Kumar Singh Nayak, Neeraja P Alamuru-Yellapragada, Kishore V L Parsa
Post translational modifications, ubiquitination and its reversal by deubiquitination play an important role in regulating innate immune system. USP12 is a poorly studied deubiquitinase reported to regulate T-cell receptor signalling however the functional role of USP12 in macrophages, the principal architects of inflammation, is unknown. Thus, in this study we probed the involvement of USP12 in macrophage mediated inflammatory responses using bacterial endotoxin, LPS, as the model system. Here, we observed that the expression of USP12 was altered in time dependent manner in LPS stimulated RAW 264...
January 4, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28062663/a-population-based-analysis-of-germline-bap1-mutations-in-melanoma
#8
Sally J O'Shea, Carla Daniela Robles-Espinoza, Lauren McLellan, Jeanine Harrigan, Xavier Jacq, James Hewinson, Vivek Iyer, Will Merchant, Faye Elliott, Mark Harland, D Timothy Bishop, Julia Newton-Bishop, David J Adams
Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found...
January 5, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28040451/regulation-of-xiap-turnover-reveals-a-role-for-usp11-in-promotion-of-tumorigenesis
#9
Zhuan Zhou, Aiping Luo, Indira Shrivastava, Mingjing He, Yi Huang, Ivet Bahar, Zhihua Liu, Yong Wan
The emerging regulatory role of deubiquitinases (DUBs) has been implicated in various fundamental processes and pathogenesis. To determine the pivotal role that DUBs play in mediating tumorigenesis, we have performed a non-biased screen of 67 human DUBs based on a mammary cell transformation assay. This led to the identification of USP11 as a critical determinant of mammary tumor initiation and progression. Using an approach of protein complex purification coupled with mass spectrometry, we further identified XIAP to be a target for USP11...
February 2017: EBioMedicine
https://www.readbyqxmd.com/read/28031360/herpes-simplex-virus-type-1-ubiquitin-specific-protease-ul36-abrogates-nf-%C3%AE%C2%BAb-activation-in-dna-sensing-signal-pathway
#10
Ruijie Ye, Chenhe Su, Haiyan Xu, Chunfu Zheng
: The DNA sensing pathway triggers innate immune responses against DNA virus infection and the NF-κB signaling plays a critical role in establishing the innate immunity. Here we report that the herpes simplex virus type 1 (HSV-1) ubiquitin-specific protease (UL36USP), which is a deubiquitinase (DUB), antagonizes the NF-κB activation, depending on its DUB activity. In this study, ectopically expressed UL36USP blocked promoter activation of interferon (IFN)-β and NF-κB induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING)...
December 28, 2016: Journal of Virology
https://www.readbyqxmd.com/read/28009280/three-dimensional-architecture-of-the-human-brca1-a-histone-deubiquitinase-core-complex
#11
Otto J P Kyrieleis, Pauline B McIntosh, Sarah R Webb, Lesley J Calder, Janette Lloyd, Nisha A Patel, Stephen R Martin, Carol V Robinson, Peter B Rosenthal, Stephen J Smerdon
BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM) reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/27999174/the-histone-deubiquitinase-otld1-targets-euchromatin-to-regulate-plant-growth
#12
Ido Keren, Vitaly Citovsky
Histone monoubiquitination is associated with active chromatin and plays an important role in epigenetic regulation of gene expression in plants. Deubiquitinating enzymes remove the ubiquitin group from histones and thereby contribute to gene repression. The Arabidopsis thaliana genome encodes 50 deubiquitinases, yet only 2 of them-UBP26 and OTLD1, members of the USP/UBP (ubiquitin-specific protease and ubiquitin-binding protein) and OTU (ovarian tumor protease) deubiquitinase families-are known to target histones...
December 20, 2016: Science Signaling
https://www.readbyqxmd.com/read/27993934/cell-cycle-regulated-ubiquitination-of-tankyrase-1-by-rnf8-and-abro1-brcc36-controls-the-timing-of-sister-telomere-resolution
#13
Ekta Tripathi, Susan Smith
Timely resolution of sister chromatid cohesion in G2/M is essential for genome integrity. Resolution at telomeres requires the poly(ADP-ribose) polymerase tankyrase 1, but the mechanism that times its action is unknown. Here, we show that tankyrase 1 activity at telomeres is controlled by a ubiquitination/deubiquitination cycle depending on opposing ubiquitin ligase and deubiquitinase activities. In late S/G2 phase, the DNA damage-responsive E3 ligase RNF8 conjugates K63-linked ubiquitin chains to tankyrase 1, while in G1 phase such ubiquitin chains are removed by BRISC, an ABRO1/BRCC36-containing deubiquitinase complex...
December 19, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27993553/screening-ubiquitin-specific-protease-activities-using-chemically-synthesized-ubiquitin-and-ubiquitinated-peptides
#14
Marine Bacchi, Benjamin Fould, Magali Jullian, Aude Kreiter, Amélie Maurras, Olivier Nosjean, Thibault Coursindel, Karine Puget, Gilles Ferry, Jean A Boutin
Ubiquitin, a 76 amino acid protein, is a key component that contributes to cellular protein homeostasis. The specificity of this modification is due to a series of enzymes: ligases, attaching the ubiquitin to a lysine, and deubiquitinases, which remove it. More than a hundred of such proteins are implicated in the regulation of protein turnover. Their specificities are only partially understood. We chemically synthesized ubiquitin, attached it to lysines belonging to the protein sequences known to be ubiquitinated...
February 15, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/27986371/mechanism-of-ubiquitination-and-deubiquitination-in-the-fanconi-anemia-pathway
#15
Sylvie van Twest, Vincent J Murphy, Charlotte Hodson, Winnie Tan, Paolo Swuec, Julienne J O'Rourke, Jörg Heierhorst, Wayne Crismani, Andrew J Deans
Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi anemia (FA). The "FA core complex" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form...
December 9, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27980214/the-isg15-specific-protease-usp18-regulates-stability-of-pten
#16
Lisa Maria Mustachio, Masanori Kawakami, Yun Lu, Jaime Rodriguez-Canales, Barbara Mino, Carmen Behrens, Ignacio Wistuba, Neus Bota-Rabassedas, Jun Yu, J Jack Lee, Jason Roszik, Lin Zheng, Xi Liu, Sarah J Freemantle, Ethan Dmitrovsky
The ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) is implicated in both oncogenic and tumor suppressive programs. Yet, few ISGylation substrates are known and functionally validated in cancer biology. We previously found specific oncoproteins were substrates of ISGylation and were stabilized by the ISG15-specific deubiquitinase (DUB) ubiquitin specific peptidase 18 (USP18). Using reverse-phase protein arrays (RPPAs), this study reports that engineered loss of the DUB USP18 destabilized the tumor suppressor protein phosphatase and tensin homologue (PTEN) in both murine and human lung cancer cell lines...
December 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27974222/usp10-is-an-essential-deubiquitinase-for-hematopoiesis-and-inhibits-apoptosis-of-long-term-hematopoietic-stem-cells
#17
Masaya Higuchi, Hiroki Kawamura, Hideaki Matsuki, Toshifumi Hara, Masahiko Takahashi, Suguru Saito, Kousuke Saito, Shuying Jiang, Makoto Naito, Hiroshi Kiyonari, Masahiro Fujii
Self-renewal, replication, and differentiation of hematopoietic stem cells (HSCs) are regulated by cytokines produced by niche cells in fetal liver and bone marrow. HSCs must overcome stresses induced by cytokine deprivation during normal development. In this study, we found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within 1 year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long-term HSCs (LT-HSCs) in bone marrow and fetal liver...
December 13, 2016: Stem Cell Reports
https://www.readbyqxmd.com/read/27974205/trpv1-nociceptor-activity-initiates-usp5-t-type-channel-mediated-plasticity
#18
Patrick Stemkowski, Agustin García-Caballero, Vinicius De Maria Gadotti, Said M'Dahoma, Shuo Huang, Stefanie Alice Gertrud Black, Lina Chen, Ivana Assis Souza, Zizhen Zhang, Gerald Werner Zamponi
Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr...
December 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27960333/synthetic-uncleavable-ubiquitinated-proteins-dissect-proteasome-deubiquitination-and-degradation-and-highlight-distinctive-fate-of-tetraubiquitin
#19
Sumeet K Singh, Indrajit Sahu, Sachitanand M Mali, Hosahalli P Hemantha, Oded Kleifeld, Michael H Glickman, Ashraf Brik
Various hypotheses have been proposed regarding how chain length, linkage type, position on substrate, and susceptibility to deubiquitinases (DUBs) affect processing of different substrates by proteasome. Here we report a new strategy for the chemical synthesis of ubiquitinated proteins to generate a set of well-defined conjugates bearing an oxime bond between the chain and the substrate. We confirmed that this isopeptide replacement is resistant to DUBs and to shaving by proteasome. Analyzing products generated by proteasomes ranked how chain length governed degradation outcome...
December 14, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27941124/a-phosphorylation-deubiquitination-cascade-regulates-the-brca2-rad51-axis-in-homologous-recombination
#20
Kuntian Luo, Lei Li, Yunhui Li, Chenming Wu, Yujiao Yin, Yuping Chen, Min Deng, Somaira Nowsheen, Jian Yuan, Zhenkun Lou
Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2-RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR...
December 1, 2016: Genes & Development
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