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Deubiquitination

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https://www.readbyqxmd.com/read/28420819/synonymous-and-biased-codon-usage-by-mers-cov-papain-like-and-3cl-proteases
#1
Mahmoud Kandeel, Abdallah Altaher
Middle East respiratory syndrome coronavirus (MERS CoV) is a recently evolved fatal respiratory disease that poses a concern for a global epidemic. MERS CoV encodes 2 proteases, 3C-like protease (3CLpro) and papain-like protease (PLpro). These proteases share in processing MERS CoV polyproteins at different sites to yield 16 nonstructural proteins. In this work, we provide evidence that MERS CoV 3CLpro and PLpro are subject to different genetic and evolutionary influences that shape the protein sequence, codon usage pattern, and codon usage bias...
April 18, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28417539/usp22-mediates-the-multidrug-resistance-of-hepatocellular-carcinoma-via-the-sirt1-akt-mrp1-signaling-pathway
#2
Sunbin Ling, Jie Li, Qiaonan Shan, Haojiang Dai, Di Lu, Xue Wen, Penghong Song, Haiyang Xie, Lin Zhou, Jimin Liu, Xiao Xu, Shusen Zheng
Drug treatments for hepatocellular carcinoma (HCC) often fail because of multidrug resistance (MDR). The mechanisms of MDR are complex but cancer stem cells (CSC), which are able to self-renew and differentiate, have recently been shown to be involved. The deubiquitinating enzyme ubiquitin-specific protease 22 (USP22) is a marker for CSCs. This study aimed to elucidate the role of USP22 in MDR of HCC and the underlying mechanisms. Using in vitro and in vivo assays, we found that modified USP22 levels were responsible for the altered drug-resistant phenotype of BEL7402 and BEL/FU cells...
April 18, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28416659/deubiquitinase-yod1-potentiates-yap-taz-activities-through-enhancing-itch-stability
#3
Youngeun Kim, Wantae Kim, Yonghee Song, Jeong-Rae Kim, Kyungjoo Cho, Hyuk Moon, Simon Weonsang Ro, Eunjeong Seo, Yeon-Mi Ryu, Seung-Jae Myung, Eek-Hoon Jho
Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination-deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28416611/the-deubiquitinating-enzyme-usp14-allosterically-inhibits-multiple-proteasomal-activities-and-ubiquitin-independent-proteolysis
#4
Hyoung Tae Kim, Alfred L Goldberg
The proteasome-associated deubiquitinating enzyme Usp14/Ubp6 inhibits protein degradation by catalyzing substrate deubiquitination and by poorly understood allosteric actions. However, upon binding a ubiquitin chain, Usp14 enhances proteasomal degradation by stimulating ATP and peptide degradation. These studies were undertaken to clarify these seemingly opposite regulatory roles of Usp14 and their importance. To learn how the presence of Usp14 on 26S proteasomes influences its different activities, we compared enzymatic and regulatory properties of 26S proteasomes purified from wild type MEF cells and ones lacking Usp14...
April 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28410891/advancing-our-understanding-of-ubiquitination-using-the-ub-toolkit
#5
REVIEW
Katharina F Witting, Monique P C Mulder, Huib Ovaa
Post-translational protein modification by ubiquitin (Ub) and ubiquitin-like modifiers (Ubl) is orchestrated by the sequential action of ubiquitin activating, conjugating, and ligating enzymes to regulate a vast array of fundamental biological processes. Unsurprisingly, the dysregulation of the intricate interplay between ubiquitination and deubiquitination gives rise to numerous pathologies, most notably cancer and neurodegenerative diseases. While activity-based probes (ABPs) and assay reagents have been extensively developed and applied for deubiquitinating enzymes (DUBs), similar tools for the ubiquitin cascade have only recently emerged...
April 11, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28396413/ubiquitinated-proteins-promote-the-association-of-proteasomes-with-the-deubiquitinating-enzyme-usp14-and-the-ubiquitin-ligase-ube3c
#6
Chueh-Ling Kuo, Alfred Lewis Goldberg
In mammalian cells, the 26S proteasomes vary in composition. In addition to the standard 28 subunits in the 20S core particle and 19 subunits in each 19S regulatory particle, a small fraction (about 10-20% in our preparations) also contains the deubiquitinating enzyme Usp14/Ubp6, which regulates proteasome activity, and the ubiquitin ligase, Ube3c/Hul5, which enhances proteasomal processivity. When degradation of ubiquitinated proteins in cells was inhibited, levels of Usp14 and Ube3c on proteasomes increased within minutes...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28391724/usp19-suppresses-cellular-type-i-interferon-signaling-by-targeting-traf3-for-deubiquitination
#7
Zhiwen Gu, Weifeng Shi, Li Zhang, Zhilin Hu, Chao Xu
AIM: To investigate host factors that mediate the immune escape of enterovirus 71 (EV71) in the context of deubiquitinating enzymes. MATERIALS & METHODS: Utilize PCR array to screen candidate genes that may be involved in EV71-induced cellular antiviral immune responses, and utilize protein mass spectrometry analysis to identify the functional targets of the candidate regulator. RESULTS: EV71 infection induces the upregulation of ubiquitin-specific protease 19 (USP19) gene expression, which negatively regulates cellular antiviral type I interferon signaling...
April 10, 2017: Future Microbiology
https://www.readbyqxmd.com/read/28389374/a-novel-brca1-associated-protein-1-isoform-affects-response-of-mesothelioma-cells-to-drugs-impairing-brca1-mediated-dna-repair
#8
Rossella Parrotta, Agata Okonska, Manuel Ronner, Walter Weder, Rolf Stahel, Lorenza Penengo, Emanuela Felley-Bosco
INTRODUCTION: BRCA1-associated protein-1, BAP1, is a tumor suppressor involved in multiple cellular processes such as transcriptional regulation, chromatin modification by deubiquitinating histone 2A and DNA repair. BAP1 mutations are frequent in malignant pleural mesothelioma (MPM). Our aim was to functionally characterize a newly identified isoform of BAP1 and investigate the effects of its expression on drug sensitivity in MPM. METHODS: Expression of BAP1 isoforms was detected by qPCR in MPM and normal mesothelium cell lines, tumor and non-tumor samples...
April 4, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28386537/revealing-a-novel-otubain-like-enzyme-from-leishmania-infantum-with-deubiquitinating-activity-toward-k48-linked-substrate
#9
Clênia S Azevedo, Bruna C Guido, Jhonata L Pereira, Diego O Nolasco, Rafael Corrêa, Kelly G Magalhães, Flávia N Motta, Jaime M Santana, Philippe Grellier, Izabela M D Bastos
Deubiquitinating enzymes (DUBs) play an important role in regulating a variety of eukaryotic processes. In this context, exploring the role of deubiquitination in Leishmania infantum could be a promising alternative to search new therapeutic targets for leishmaniasis. Here we present the first characterization of a DUB from L. infantum, otubain (OtuLi), and its localization within parasite. The recombinant OtuLi (rOtuLi) showed improved activity on lysine 48 (K48)-linked over K63-linked tetra-ubiquitin (Ub) and site-directed mutations on amino acids close to the catalytic site (F82) or involved in Ub interaction (L265 and F182) caused structural changes as shown by molecular dynamics, resulting in a reduction or loss of enzyme activity, respectively...
2017: Frontiers in Chemistry
https://www.readbyqxmd.com/read/28382714/enzyme-reversal-to-explore-the-function-of-yeast-e3-ubiquitin-ligases
#10
Chris MacDonald, Stanley Winistorfer, R Marshall Pope, Michael E Wright, Robert C Piper
The covalent attachment of ubiquitin onto proteins can elicit a variety of downstream consequences. Attachment is mediated by a large array of E3 ubiquitin ligases, each thought be subject to regulatory control and to have a specific repertoire of substrates. Assessing the biological roles of ligases, and in particular, identifying their biologically relevant substrates has been a persistent yet challenging question. In this study we describe tools that may help achieve both of these goals. We describe a strategy whereby the activity of a ubiquitin ligase has been enzymatically reversed, accomplished by fusing it to a catalytic domain of an exogenous deubiquitinating enzyme...
April 6, 2017: Traffic
https://www.readbyqxmd.com/read/28381987/the-ubiquitination-disaggregation-and-proteasomal-degradation-machineries-in-polyglutamine-disease
#11
REVIEW
Samir R Nath, Andrew P Lieberman
Polyglutamine disorders are chronic, progressive neurodegenerative diseases caused by expansion of a glutamine tract in widely expressed genes. Despite excellent models of disease, a well-documented clinical history and progression, and established genetic causes, there are no FDA approved, disease modifying treatments for these disorders. Downstream of the mutant protein, several divergent pathways of toxicity have been identified over the last several decades, supporting the idea that targeting only one of these pathways of toxicity is unlikely to robustly alleviate disease progression...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28381482/usp26-regulates-tgf-%C3%AE-signaling-by-deubiquitinating-and-stabilizing-smad7
#12
Sarah Kit Leng Lui, Prasanna Vasudevan Iyengar, Patrick Jaynes, Zul Fazreen Bin Adam Isa, Brendan Pang, Tuan Zea Tan, Pieter Johan Adam Eichhorn
The amplitude of transforming growth factor-β (TGF-β) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF-β signaling acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF-β receptor complex for ubiquitin-mediated degradation. Here, we identify the deubiquitinating enzyme USP26 as a novel integral component of this negative feedback loop. We demonstrate that TGF-β rapidly enhances the expression of USP26 and reinforces SMAD7 stability by limiting the ubiquitin-mediated turnover of SMAD7...
April 5, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28380042/genetic-and-pharmacological-inhibition-of-ttk-impairs-pancreatic-cancer-cell-line-growth-by-inducing-lethal-chromosomal-instability
#13
Jeran K Stratford, Feng Yan, Rebecca A Hill, Michael B Major, Lee M Graves, Channing J Der, Jen Jen Yeh
Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1)...
2017: PloS One
https://www.readbyqxmd.com/read/28365890/expressions-of-insulin-like-growth-factor-receptor-1-and-cezanne-1-in-lung-adenocarcinoma
#14
Zhaofei Pang, Lixuan Cui, Nan Ding, Linhai Zhu, Xiao Qu, Wei Dong, Jiajun Du, Qi Liu
IGF1R (insulin-like growth factor receptor-1) was confirmed to play a significant role in the development of cancer. Cezanne-1 overexpression was considered to be associated with enhancement of EGFR signaling pathway and reduced degeneration of EGFR. There was a close relationship between EGFR and IGFR as previous study showed. Dynamic balance between receptor ubiquitination and deubiquitination was critical in the process of termination of IGF signaling pathway. So we conducted an IHC staining to initially prove the correlation...
May 2017: Medical Oncology
https://www.readbyqxmd.com/read/28363942/usp49-negatively-regulates-tumorigenesis-and-chemoresistance-through-fkbp51-akt-signaling
#15
Kuntian Luo, Yunhui Li, Yujiao Yin, Lei Li, Chenming Wu, Yuping Chen, Somaira Nowsheen, Qi Hu, Lizhi Zhang, Zhenkun Lou, Jian Yuan
The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway...
March 31, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28362430/cyld-a20-and-otulin-deubiquitinases-in-nf-%C3%AE%C2%BAb-signaling-and-cell-death-so-similar-yet-so-different
#16
REVIEW
Marie Lork, Kelly Verhelst, Rudi Beyaert
Polyubiquitination of proteins has a pivotal role in the regulation of numerous cellular functions such as protein degradation, DNA repair and cell signaling. As deregulation of these processes can result in pathological conditions such as inflammatory diseases, neurodegeneration or cancer, tight regulation of the ubiquitin system is of tremendous importance. Ubiquitination by E3 ubiquitin ligases can be counteracted by the activity of several deubiquitinating enzymes (DUBs). CYLD, A20 and OTULIN have been implicated as key DUBs in the negative regulation of NF-κB transcription factor-mediated gene expression upon stimulation of cytokine receptors, antigen receptors and pattern recognition receptors, by removing distinct types of polyubiquitin chains from specific NF-κB signaling proteins...
March 31, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28355105/josd1-negatively-regulates-type-i-interferon-antiviral-activity-by-deubiquitinating-and-stabilizing-socs1
#17
Xiaofang Wang, Liting Zhang, Yunli Zhang, Peng Zhao, Liping Qian, Yukang Yuan, Jin Liu, Qiao Cheng, Wenqian Xu, Yibo Zuo, Tingting Guo, Zhengyuan Yu, Hui Zheng
The Josephin domain-containing (JOSD) protein 1 (JOSD1) is recognized as one member of deubiquitinases (DUBs) due to its catalytic "Josephin" domain. However, the in vivo deubiquitinating activity of JOSD1 remains unidentified, and the biological functions of JOSD1 are largely unknown. In this study, we report that JOSD1 plays an important role in regulating type-I interferon (IFN-I)-mediated antiviral activity. JOSD1 physically interacts with SOCS1, which is an essential negative regulator of many cytokines signaling, and enhances SOCS1 stability by deubiquitinating K48-linked polyubiquitination of SOCS1...
March 29, 2017: Viral Immunology
https://www.readbyqxmd.com/read/28350092/deubiquitinating-enzyme-usp20-is-a-positive-regulator-of-claspin-and-suppresses-the-malignant-characteristics-of-gastric-cancer-cells
#18
Chao Wang, Chen Yang, Jun Ji, Jinling Jiang, Min Shi, Qu Cai, Yingyan Yu, Zhenggang Zhu, Jun Zhang
The aim of the present study was to investigate the clinical significance, the biological function and the mechanisms of USP20 in gastric cancer. The expression of USP20 in 89 pairs of primary gastric cancer and peritumoral gastric tissues specimens were measured by immunohistochemistry. The correlation of USP20 expression with the survival and the clinicopathological characteristics of patients were analyzed. Moreover, the underlying mechanisms of ectopic USP20 expression and its impact on GC cells were also investigated...
March 8, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28348081/the-herpes-simplex-virus-1-ul36usp-deubiquitinase-suppresses-dna-repair-in-host-cells-via-deubiquitination-of-proliferating-cell-nuclear-antigen
#19
Xiaodong Dong, Junhong Guan, Chunfu Zheng, Xiaofeng Zheng
Herpes simplex virus 1 (HSV-1) infection manipulates distinct host DNA damage responses (DDR) to facilitate virus proliferation, but the molecular mechanisms remain to be elucidated. One possible HSV-1 target might be DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS) pathway. In TLS, proliferating cell nuclear antigen (PCNA) is monoubiquitinated in response to DNA damage-caused replication fork stalling. Ubiquitinated PCNA then facilitates the error-prone DNA polymerase eta (pol eta)-mediated TLS, allowing the fork to bypass damaged sites...
March 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28347402/chlamydia-trachomatis-containing-vacuole-serves-as-deubiquitination-platform-to-stabilize-mcl-1-and-to-interfere-with-host-defense
#20
Annette Fischer, Kelly S Harrison, Yesid Ramirez, Daniela Auer, Suvagata Roy Chowdhury, Bhupesh K Prusty, Florian Sauer, Zoe Dimond, Caroline Kisker, P Scott Hefty, Thomas Rudel
Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion...
March 28, 2017: ELife
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