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Ubiquitin-specific protease

Kathrin Kunz, Tanja Piller, Stefan Müller
The ubiquitin-related SUMO system controls many cellular signaling networks. In mammalian cells, three SUMO forms (SUMO1, SUMO2 and SUMO3) act as covalent modifiers of up to thousands of cellular proteins. SUMO conjugation affects cell function mainly by regulating the plasticity of protein networks. Importantly, the modification is reversible and highly dynamic. Cysteine proteases of the sentrin-specific protease (SENP) family reverse SUMO conjugation in mammalian cells. In this Cell Science at a Glance article and the accompanying poster, we will summarize how the six members of the mammalian SENP family orchestrate multifaceted deconjugation events to coordinate cell processes, such as gene expression, the DNA damage response and inflammation...
March 20, 2018: Journal of Cell Science
Karin Kosulin, Elena Lam, Albert Heim, Thomas Dobner, Estefanía Rodríguez
BACKGROUND: Human adenoviral (HAdV) infections are usually mild and self-limited, however, some infections from species A, B, C, D and E, can cause severe illnesses, which have raised public health concerns over the past few years. Current available antiviral therapies have limited efficacy and severe toxicity; therefore, finding new targets for specific anti-adenoviral drug design is urgently needed. Our previous work showed that the small molecule compound, HBX, inhibits HAdV type 5 (species C, HAdV-C5) replication and oncogenic transformation through inhibition of the cellular pro-viral factor ubiquitin-specific protease 7 (USP7)...
March 20, 2018: Antiviral Therapy
Sheng Zhang, Chengrong Xie, Honghe Li, Kang Zhang, Jie Li, Xiaomin Wang, Zhenyu Yin
Ubiquitin-specific protease 11 (USP11) is a deubiquitinating enzyme that exerts its biological functions by regulating multiple signaling pathways such as p53, NF-κB, TGF-β, and Hippo. A large body of evidence supports a link between UPS11 and tumorigenesis. However, the clinical significance and biological function of USP11 in hepatocellular carcinoma (HCC) remains unclear. Here, USP11 expression was assessed by immunohistochemistry in a pilot series of 71 HCC clinical samples, and the association between USP11 expression and clinicopathological features and overall survival time was analyzed...
March 15, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Kati Richter, Teija Paakkola, Daniela Mennerich, Kateryna Kubaichuk, Anja Konzack, Heidi Ali-Kippari, Nina Kozlova, Peppi Koivunen, Kirsi-Maria Haapasaari, Arja Jukkola-Vuorinen, Hanna-Riikka Teppo, Elitsa Y Dimova, Risto Bloigu, Zoltan Szabo, Risto Kerkelä, Thomas Kietzmann
Recent studies suggest that the ubiquitin-specific protease USP28 plays an important role in cellular repair and tissue remodeling, which implies that it has a direct role in carcinogenesis. The carcinogenic potential of USP28 was investigated in a comprehensive manner using patients, animal models, and cell culture. The findings demonstrate that overexpression of USP28 correlates with a better survival in patients with invasive ductal breast carcinoma. Mouse xenograft experiments with USP28-deficient breast cancer cells also support this view...
March 15, 2018: Molecular Cancer Research: MCR
Tomoko Kubori, Tomoe Kitao, Hiroki Ando, Hiroki Nagai
The intracellular bacterial pathogen Legionella pneumophila establishes the replicative niche as a result of the actions of a large array of effector proteins delivered via the Legionella type IV secretion system (T4SS). Many effector proteins are expected to be involved in biogenesis and regulation of the Legionella-containing vacuole (LCV) that is highly decorated with ubiquitin. Here, we identified a Legionella deubiquitinase (DUB), designated LotA, by carrying out a genome analysis to find proteins resembling the eukaryotic ovarian tumor (OTU) superfamily of cysteine proteases...
March 15, 2018: Cellular Microbiology
Colin R O'Dowd, Matthew D Helm, J S Shane Rountree, Jakub T Flasz, Elias Arkoudis, Hugues Miel, Peter R Hewitt, Linda Jordan, Oliver Barker, Caroline Hughes, Ewelina Rozycka, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Stephanie Feutren-Burton, Scarlett Dvorkin, Gerald Gavory, Timothy Harrison
Ubiquitin specific protease 7 (USP7, HAUSP) has become an attractive target in drug discovery due to the role it plays in modulating Mdm2 levels and consequently p53. Increasing interest in USP7 is emerging due to its potential involvement in oncogenic pathways as well as possible roles in both metabolic and immune disorders in addition to viral infections. Potent, novel, and selective inhibitors of USP7 have been developed using both rational and structure-guided design enabled by high-resolution cocrystallography...
March 8, 2018: ACS Medicinal Chemistry Letters
Tryphena Adams, Nana Aba A Ennuson, Neils B Quashie, Godfred Futagbi, Sena Matrevi, Oheneba C K Hagan, Benjamin Abuaku, Kwadwo A Koram, Nancy O Duah
BACKGROUND: Plasmodium falciparum delayed clearance with the use of artemisinin-based combination therapy (ACTs) has been reported in some African countries. Single nucleotide polymorphisms (SNPs) in two genes, P. falciparum adaptor protein complex 2 mu subunit (pfap2mu) and ubiquitin specific protease 1 (pfubp1), have been linked to delayed clearance with ACT use in Kenya and recurrent imported malaria in Britain. With over 12 years of ACT use in Ghana, this study investigated the prevalence of SNPs in the pfap2mu and pfubp1 in Ghanaian clinical P...
March 12, 2018: Parasites & Vectors
Marcin D Tomala, Katarzyna Magiera-Mularz, Katarzyna Kubica, Sylwia Krzanik, Bartosz Zieba, Bogdan Musielak, Marcin Pustula, Grzegorz M Popowicz, Michael Sattler, Grzegorz Dubin, Lukasz Skalniak, Tad A Holak
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a...
March 5, 2018: European Journal of Medicinal Chemistry
Guanghui Qian, Xiaohan Hu, Gen Li, Yueyue Ding, Liyan Zhu, Hui Zheng, Mei Li, Zhiheng Li, Jian Pan, Yiping Li, Gang Li, Chun Yang, Ying Liu, Yi Xie, Haitao Lv
Protein ubiquitination and deubiquitination enzymes are widely involved in innate immune responses. The ubiquitin specific protease 25 (USP25), a deubiquitinating enzyme, has been demonstrated to play an important role in virus infection and immunity. However, how USP25 is degraded and regulated by E3 ubiquitin ligases remains poorly understood. Here, we identified Smad ubiquitin regulatory factor 1(Smurf1) as a first novel E3 ubiquitin ligase of USP25. Smurf1 overexpression decreases USP25 protein turnover, and the E3 ligase enzymatic activity of Smurf1 is required for USP25 degradation...
March 5, 2018: Biochemical and Biophysical Research Communications
Alexander Beck, Franziska Trippel, Alexandra Wagner, Saskia Joppien, Max Felle, Christian Vokuhl, Thomas Schwarzmayr, Tim M Strom, Dietrich von Schweinitz, Gernot Längst, Roland Kappler
Background: Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification. Results: We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB...
2018: Clinical Epigenetics
Mohammad Ali, Edward S Mocarski
Proteasome inhibitors have achieved clinical success because they trigger intrinsic and extrinsic cell death to eliminate susceptible human cancers. The ubiquitin-proteasome protein degradation system regulates signaling pathways by controlling levels of components such as cellular inhibitor of apoptosis (cIAP)1 and cIAP2 in TNF-mediated cell death. Here, we sought to evaluate the contribution of necroptosis to the cell death pattern induced by the specific proteasome inhibitor Carfilzomib (Cf). Proteasome inhibitor-sensitive multiple myeloma cell lines die in response to Cf by apoptosis in combination with serine protease-dependent death, without any contribution of RIPK3-dependent necroptosis...
March 1, 2018: Cell Death & Disease
Jun Hwan Kim, Dongyeob Seo, Sun-Jick Kim, Dong Wook Choi, Jin Seok Park, Jihoon Ha, Jungwon Choi, Ji-Hyung Lee, Su Myung Jung, Kyoung-Wan Seo, Eun-Woo Lee, Youn Sook Lee, Heesun Cheong, Cheol Yong Choi, Seok Hee Park
Autophagy begins with the formation of autophagosomes, a process that depends on the activity of the serine/threonine kinase ULK1 (hATG1). Although earlier studies indicated that ULK1 activity is regulated by dynamic polyubiquitination, the deubiquitinase involved in the regulation of ULK1 remained unknown. In this study, we demonstrate that ubiquitin-specific protease 20 (USP20) acts as a positive regulator of autophagy initiation through stabilizing ULK1. At basal state, USP20 binds to and stabilizes ULK1 by removing the ubiquitin moiety, thereby interfering with the lysosomal degradation of ULK1...
February 27, 2018: EMBO Reports
Olya Yarychkivska, Omid Tavana, Wei Gu, Timothy H Bestor
BACKGROUND: It has been reported that USP7 (ubiquitin-specific protease 7) prevents ubiquitylation and degradation of DNA methyltransferase 1 (DNMT1) by direct binding of USP7 to the glycine-lysine (GK) repeats that join the N-terminal regulatory domain of DNMT1 to the C-terminal methyltransferase domain. The USP7-DNMT1 interaction was reported to be mediated by acetylation of lysine residues within the (GK) repeats. RESULTS: We found that DNMT1 is present at normal levels in mouse and human cells that contain undetectable levels of USP7...
February 27, 2018: Epigenetics & Chromatin
Masamitsu Inoue, Yuki Hitora, Hikaru Kato, Fitje Losung, Remy E P Mangindaan, Sachiko Tsukamoto
Four new geranyl flavonoids 1-4 and four known flavonoids 5-8 were obtained from the leaves of Artocarpus communis collected in Indonesia. The planar structures of flavonoids were elucidated by analyses of MS and NMR spectroscopic data. Absolute configurations of 1 and 2 were determined by ECD spectroscopy. Analyses by HPLC with a chiral-phase column and ECD spectra confirmed that 3 and 4 were stereoisomeric mixtures and 7 and 8 were racemic mixtures. The compounds obtained in this study inhibited the enzymatic activities of ubiquitin-specific protease 7 (USP7) and the chymotrypsin-like activity of the proteasome...
February 24, 2018: Journal of Natural Medicines
Thomas Hermanns, Christian Pichlo, Ilka Woiwode, Karsten Klopffleisch, Katharina F Witting, Huib Ovaa, Ulrich Baumann, Kay Hofmann
Deubiquitinating enzymes (DUBs) regulate ubiquitin signaling by trimming ubiquitin chains or removing ubiquitin from modified substrates. Similar activities exist for ubiquitin-related modifiers, although the enzymes involved are usually not related. Here, we report human ZUFSP (also known as ZUP1 and C6orf113) and fission yeast Mug105 as founding members of a DUB family different from the six known DUB classes. The crystal structure of human ZUFSP in covalent complex with propargylated ubiquitin shows that the DUB family shares a fold with UFM1- and Atg8-specific proteases, but uses a different active site more similar to canonical DUB enzymes...
February 23, 2018: Nature Communications
Aram Ko, Su Yeon Han, Chel Hun Choi, Hanbyoul Cho, Min-Sik Lee, Soo-Youl Kim, Joon Seon Song, Kyeong-Man Hong, Han-Woong Lee, Stephen M Hewitt, Joon-Yong Chung, Jaewhan Song
Oncogene-induced senescence (OIS) is a critical tumor-suppressor mechanism, which prevents hyper-proliferation and transformation of cells. c-Myc promotes OIS through the transcriptional activation of p14ARF followed by p53 activation. Although the oncogene-mediated transcriptional regulation of p14ARF has been well addressed, the post-translational modification of p14ARF regulated by oncogenic stress has yet to be investigated. Here, we found that c-Myc increased p14ARF protein stability by inducing the transcription of ubiquitin-specific protease 10 (USP10)...
February 22, 2018: Cell Death and Differentiation
Ke Xu, Hua Pei, Zhenhao Zhang, Huamin Wang, Liang Li, Qianfeng Xia
Glioblastoma multiforme (GBM) is one of the most aggressive types of brain tumor worldwide. Despite the advances made in treatment and research, the median survival time for GBM patients remains <1.5 years, providing impetus for the identification of potential novel therapeutic target genes to improve GBM treatment. The deubiquitinating enzyme ubiquitin specific peptidase 15 (USP15) has emerged as a pro-oncogenic factor; however, its function in GBM has yet to be fully elucidated. The present study sought to determine whether or not USP15 is implicated in GBM cell invasion and proliferation...
March 2018: Oncology Letters
Shang-Ju Chuang, Shu-Chun Cheng, Hui-Chi Tang, Chiao-Yin Sun, Chi-Yuan Chou
Ubiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells' survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2...
February 15, 2018: Scientific Reports
Yanxin Su, Peidian Shi, Lilin Zhang, Dong Lu, Chengxue Zhao, Ruiqiao Li, Lei Zhang, Jinhai Huang
Linear ubiquitination plays an important role in the regulation of the immune response by regulating the nuclear factor κB (NF-κB). The linear ubiquitin-specific deubiquitinase OTULIN can control immune signaling transduction pathway by restricting Met1-linked ubiquitination process. In our study, the porcine OTLLIN gene was cloned and deubiquitin functions were detected in PRRSV-infected cell model. PRRSV infection promotes the expression of OTULIN gene, in turn, overexpression of OTULIN contributes to PRRSV proliferation...
February 14, 2018: Journal of Virology
Andrew B Fielding, Matthew Concannon, Sarah Darling, Emma V Rusilowicz-Jones, Joseph J Sacco, Ian A Prior, Michael J Clague, Sylvie Urbé, Judy M Coulson
Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges...
February 12, 2018: Oncogene
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