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Deubiquitinase

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https://www.readbyqxmd.com/read/28343940/lithocholic-acid-hydroxyamide-destabilizes-cyclin-d1-and-induces-g0-g1-arrest-by-inhibiting-deubiquitinase-usp2a
#1
Katarzyna Magiera, Marcin Tomala, Katarzyna Kubica, Virginia De Cesare, Matthias Trost, Bartosz J Zieba, Neli Kachamakova-Trojanowska, Marcin Les, Grzegorz Dubin, Tad A Holak, Lukasz Skalniak
USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression...
March 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28338014/entropic-stabilization-of-a-deubiquitinase-provides-conformational-plasticity-and-slow-unfolding-kinetics-beneficial-for-functioning-on-the-proteasome
#2
Yun-Tzai Cloud Lee, Chia-Yun Chang, Szu-Yu Chen, Yun-Ru Pan, Meng-Ru Ho, Shang-Te Danny Hsu
Human ubiquitin C-terminal hydrolyase UCH-L5 is a topologically knotted deubiquitinase that is activated upon binding to the proteasome subunit Rpn13. The length of its intrinsically disordered cross-over loop is essential for substrate recognition. Here, we showed that the catalytic domain of UCH-L5 exhibits higher equilibrium folding stability with an unfolding rate on the scale of 10(-8) s(-1), over four orders of magnitudes slower than its paralogs, namely UCH-L1 and -L3, which have shorter cross-over loops...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28336234/ubiquitin-specific-protease-4-usp4-suppresses-myoblast-differentiation-by-down-regulating-myod-activity-in-a-catalytic-independent-manner
#3
Sun-Il Yun, Kyeong Kyu Kim
For myotube formation, proliferation and differentiation of myoblasts must be tightly regulated by various myogenic regulatory factors (MRFs) such as MyoD, myogenic factor 5 (Myf5), myogenin, and muscle-specific regulatory factor 4 (MRF4). However, it is not clear how the expression or activity of these MRFs is controlled during myogenesis. In this study, we identified ubiquitin-specific protease 4 (USP4), one of deubiquitinating enzymes, as a suppressor of MRFs by demonstrating that a knockdown of USP4 enhances myogenesis by controlling MyoD and the level of myogenesis marker proteins in C2C12 cells...
March 20, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28335430/a-review-on-ubiquitination-of-neurotrophin-receptors-facts-and-perspectives
#4
REVIEW
Julia Sánchez-Sánchez, Juan Carlos Arévalo
Ubiquitination is a reversible post-translational modification involved in a plethora of different physiological functions. Among the substrates that are ubiquitinated, neurotrophin receptors (TrkA, TrkB, TrkC, and p75(NTR)) have been studied recently. TrkA is the most studied receptor in terms of its ubiquitination, and different E3 ubiquitin ligases and deubiquitinases have been implicated in its ubiquitination, whereas not much is known about the other neurotrophin receptors aside from their ubiquitination...
March 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28327663/tandem-uims-confer-lys48-ubiquitin-chain-substrate-preference-to-deubiquitinase-usp25
#5
Kohei Kawaguchi, Kazune Uo, Toshiaki Tanaka, Masayuki Komada
Ubiquitin-specific protease (USP) 25, belonging to the USP family of deubiquitinases, harbors two tandem ubiquitin-interacting motifs (UIMs), a ~20-amino-acid α-helical stretch that binds to ubiquitin. However, the role of the UIMs in USP25 remains unclear. Here we show that the tandem UIM region binds to Lys48-, but not Lys63-, linked ubiquitin chains, where the two UIMs played a critical and cooperative role. Purified USP25 exhibited higher ubiquitin isopeptidase activity to Lys48-, than to Lys63-, linked ubiquitin chains...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28319114/internally-tagged-ubiquitin-a-tool-to-identify-linear-polyubiquitin-modified-proteins-by-mass-spectrometry
#6
Katarzyna Kliza, Christoph Taumer, Irene Pinzuti, Mirita Franz-Wachtel, Simone Kunzelmann, Benjamin Stieglitz, Boris Macek, Koraljka Husnjak
Ubiquitination controls a plethora of cellular processes. Modifications by linear polyubiquitin have so far been linked with acquired and innate immunity, lymphocyte development and genotoxic stress response. Until now, a single E3 ligase complex (LUBAC), one specific deubiquitinase (OTULIN) and a very few linear polyubiquitinated substrates have been identified. Current methods for studying lysine-based polyubiquitination are not suitable for the detection of linear polyubiquitin-modified proteins. Here, we present an approach to discovering linear polyubiquitin-modified substrates by combining a lysine-less internally tagged ubiquitin (INT-Ub...
March 20, 2017: Nature Methods
https://www.readbyqxmd.com/read/28315321/the-functional-interplay-between-the-hif-pathway-and-the-ubiquitin-system-more-than-a-one-way-road
#7
Julia Günter, Amalia Ruiz-Serrano, Christina Pickel, Roland H Wenger, Carsten C Scholz
The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue functions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalysed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage...
March 14, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28300829/cystatin-sn-inhibits-auranofin-induced-cell-death-by-autophagic-induction-and-ros-regulation-via-glutathione-reductase-activity-in-colorectal-cancer
#8
Byung Moo Oh, Seon-Jin Lee, Hee Jun Cho, Yun Sun Park, Jong-Tae Kim, Suk Ran Yoon, Sang Chul Lee, Jong-Seok Lim, Bo-Yeon Kim, Yong-Kyung Choe, Hee Gu Lee
Cystatin SN (CST1) is a specific inhibitor belonging to the cystatin superfamily that controls the proteolytic activities of cysteine proteases such as cathepsins. Our previous study showed that high CST1 expression enhances tumor metastasis and invasiveness in colorectal cancer. Recently, auranofin (AF), a gold(I)-containing thioredoxin reductase 1 (TrxR1) inhibitor, has been used clinically to treat rheumatoid arthritis. AF is a proteasome-associated deubiquitinase inhibitor and can act as an anti-tumor agent...
March 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28295222/traf3-cyld-mutations-identify-a-distinct-subset-of-human-papilloma-virus-associated-head-and-neck-squamous-cell-carcinoma
#9
Michael Hajek, Andrew Sewell, Susan Kaech, Barbara Burtness, Wendell G Yarbrough, Natalia Issaeva
BACKGROUND: The incidence of human papillomavirus (HPV)-associated (HPV-positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise. Newly diagnosed HPV-positive HNSCCs in the United States currently outnumber any other HPV-associated cancers, including cervical cancer. Despite introduction of the HPV vaccine, the epidemic of HPV-positive HNSCC is expected to continue for approximately 60 years. Compared with patients who have tobacco-associated HNSCC, those who have HPV-positive HNSCC have better overall survival and response to treatment...
March 13, 2017: Cancer
https://www.readbyqxmd.com/read/28291339/ubiquitin-chain-enrichment-middle-down-mass-spectrometry-ubichem-ms-enables-characterization-of-branched-ubiquitin-chains-in-cellulo
#10
Sean O Crowe, Ambar S J B Rana, Kirandeep K Deol, Ying Ge, Eric R Strieter
Ubiquitin has a broad functional range that has been ascribed to the formation of an array of polymeric ubiquitin chains. Understanding the precise roles of ubiquitin chains, however, is difficult due to their complex chain topologies. Branched ubiquitin chains are particularly challenging, as multiple modifications on a single ubiquitin preclude the use of standard bottom-up proteomic approaches. Developing methods to overcome these challenges is crucial considering evidence suggesting branched chains regulate the stability of proteins...
March 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28282038/spata2-more-than-a-missing-link
#11
Lisa Schlicher, Prisca Brauns-Schubert, Florian Schubert, Ulrich Maurer
The assembly of the TNFR1 signalling complex (TNF-RSC) depends on K63- and M1-linked ubiquitylation, promoting the recruitment of complex constituents and the stability of the complex. Ubiquitylation is a dynamic process, controlled by E3 ubiquitin ligases as well as deubiquitinases, such as CYLD and OTULIN. A novel molecule, SPATA2, which is crucial for recruiting and activating the deubiquitinase CYLD within the TNF-RSC, has now been identified by four different studies. Loss of SPATA2 was shown to result in increased TNF-, but also NOD2-mediated proinflammatory signalling...
March 10, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28280111/usp7-deubiquitinase-controls-hiv-1-production-by-stabilizing-tat-protein
#12
Amjad Ali, Rameez Raja, Sabihur Rahman Farooqui, Shaista Ahmad, Akhil C Banerjea
Deubiquitinases (DUBs) are key regulators of complex cellular processes.  HIV-1 Tat is synthesized early after infection and is mainly responsible for enhancing viral production. Here, we report that one of the DUBs, USP7, stabilized HIV-1 Tat protein through its deubiquitination. Treatment with either general DUB inhibitor (PR-619) or USP7-specific inhibitor (P5091) resulted in Tat protein degradation. USP7-specific inhibitor reduced virus production in latently infected T-lymphocytic cell line J1.1, which produces large amounts of HIV-1 upon stimulation...
March 9, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28248089/mapping-novel-metabolic-nodes-targeted-by-anti-cancer-drugs-that-impair-triple-negative-breast-cancer-pathogenicity
#13
Lindsay S Roberts, Peter Yan, Leslie A Bateman, Daniel K Nomura
Triple-negative breast cancers (TNBCs) are estrogen receptor, progesterone receptor, and HER2 receptor-negative subtypes of breast cancers that show the worst prognoses and lack targeted therapies. Here, we have coupled the screening of ~400 anti-cancer agents that are under development or in the clinic with chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair TNBC pathogenicity. We identify 20 anti-cancer compounds that significantly impaired cell survival across multiple types of TNBC cells...
March 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28245560/the-regulations-of-deubiquitinase-usp15-and-its-pathophysiological-mechanisms-in-diseases
#14
REVIEW
Chon-Kit Chou, Yu-Ting Chang, Michal Korinek, Yei-Tsung Chen, Ya-Ting Yang, Steve Leu, I-Ling Lin, Chin-Ju Tang, Chien-Chih Chiu
Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain...
February 24, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28242811/deubiquitinase-usp18-loss-mislocalizes-and-destabilizes-kras-in-lung-cancer
#15
Lisa Maria Mustachio, Yun Lu, Laura J Tafe, Vincent Memoli, Jaime Rodriguez-Canales, Barbara Mino, Pamela Andrea Villalobos, Ignacio Wistuba, Hiroyuki Katayama, Samir M Hanash, Jason Roszik, Masanori Kawakami, Kwang-Jin Cho, John F Hancock, Fadzai Chinyengetere, Shanhu Hu, Xi Liu, Sarah J Freemantle, Ethan Dmitrovsky
KRAS is frequently mutated in lung cancers and is associated with aggressive biology and chemotherapy resistance. Therefore, innovative approaches are needed to treat these lung cancers. Prior work implicated the interferon-stimulated gene 15 (ISG15) deubiquitinase (DUB) USP18 as having anti-neoplastic activity by regulating lung cancer growth and oncoprotein stability. This study demonstrates that USP18 affects the stability of the KRAS oncoprotein. Interestingly, loss of USP18 reduced KRAS expression and engineered gain of USP18 expression increased KRAS protein levels in lung cancer cells...
February 27, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28216291/ovarian-tumor-domain-containing-protein-1-deubiquitinates-and-stabilizes-p53
#16
Shudong Piao, Han Zhong Pei, Bin Huang, Suk-Hwan Baek
Ubiquitination and deubiquitination pathways play important roles in the regulation of p53 stability and activity. p53 is ubiquitinated and destabilized by E3 ubiquitin ligases and is deubiquitinated and stabilized by deubiquitinases (DUBs). We screened ovarian tumor (OTU) subfamily proteins to identify novel DUBs that stabilized p53. OTU domain-containing protein 1 (OTUD1) is a DUB belonging to the OTU family; however, its substrates and its role in cells are unknown. Here, we used an overexpression and knockdown system to show that OTUD1 is a novel regulator of p53 stability...
February 13, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28212404/the-pineal-gland-a-model-for-adrenergic-modulation-of-ubiquitin-ligases
#17
Jerry Vriend, Wenjun Liu, Russel J Reiter
INTRODUCTION: A recent study of the pineal gland of the rat found that the expression of more than 3000 genes showed significant day/night variations (The Hartley dataset). The investigators of this report made available a supplemental table in which they tabulated the expression of many genes that they did not discuss, including those coding for components of the ubiquitin proteasome system. Herein we identify the genes of the ubiquitin proteasome system whose expression were significantly influenced by environmental lighting in the Hartley dataset, those that were stimulated by DBcAMP in pineal glands in culture, and those that were stimulated by norepinephrine...
2017: PloS One
https://www.readbyqxmd.com/read/28202764/trim25-is-required-for-the-antiviral-activity-of-zinc-finger-antiviral-protein-zap
#18
Xiaojiao Zheng, Xinlu Wang, Fan Tu, Qin Wang, Zusen Fan, Guangxia Gao
Zinc-finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mRNAs, and repressing the translation and/or promoting the degradation of target mRNA. In addition, ZAP regulates the expression of certain cellular genes. Here, we report that tripartite motif-containing protein 25 (TRIM25), a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 abolished ZAP's antiviral activity. The E3 ligase activity of TRIM25 is required for this regulation...
February 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28202673/molecular-architecture-of-polycomb-repressive-complexes
#19
REVIEW
Emily C Chittock, Sebastian Latwiel, Thomas C R Miller, Christoph W Müller
The polycomb group (PcG) proteins are a large and diverse family that epigenetically repress the transcription of key developmental genes. They form three broad groups of polycomb repressive complexes (PRCs) known as PRC1, PRC2 and Polycomb Repressive DeUBiquitinase, each of which modifies and/or remodels chromatin by distinct mechanisms that are tuned by having variable compositions of core and accessory subunits. Until recently, relatively little was known about how the various PcG proteins assemble to form the PRCs; however, studies by several groups have now allowed us to start piecing together the PcG puzzle...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28198400/ubiquitin-c-terminal-hydrolase37-regulates-tcf7-dna-binding-for-the-activation-of-wnt-signalling
#20
Wonhee Han, Hyeyoon Lee, Jin-Kwan Han
The Tcf/Lef family of transcription factors mediates the Wnt/β-catenin pathway that is involved in a wide range of biological processes, including vertebrate embryogenesis and diverse pathogenesis. Post-translational modifications, including phosphorylation, sumoylation and acetylation, are known to be important for the regulation of Tcf/Lef proteins. However, the importance of ubiquitination and ubiquitin-mediated regulatory mechanisms for Tcf/Lef activity are still unclear. Here, we newly show that ubiquitin C-terminal hydrolase 37 (Uch37), a deubiquitinase, interacts with Tcf7 (formerly named Tcf1) to activate Wnt signalling...
February 15, 2017: Scientific Reports
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