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Ubiquitin-specific protease

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https://www.readbyqxmd.com/read/29146736/quantitative-high-throughput-screening-identifies-cytoprotective-molecules-that-enhance-sumo-conjugation-via-the-inhibition-of-sumo-specific-protease-senp-2
#1
Joshua D Bernstock, Daniel Ye, Jayden A Smith, Yang-Ja Lee, Florian A Gessler, Adam Yasgar, Jennifer Kouznetsova, Ajit Jadhav, Zhuoran Wang, Stefano Pluchino, Wei Zheng, Anton Simeonov, John M Hallenbeck, Wei Yang
The development of novel neuroprotective treatments for acute stroke has been fraught with failures, which supports the view of ischemic brain damage as a highly complex multifactorial process. Post-translational modifications such as small ubiquitin-like modifier (SUMO)ylation have emerged as critical molecular regulatory mechanisms in states of both homeostasis and ischemic stress, as evidenced by our previous work. Accordingly, the clinical significance of the selective control of the global SUMOylation process has become apparent in studies of ischemic pathobiology and pathophysiology...
November 16, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29138532/ubiquitin-specific-protease-2-modulates-the-lipopolysaccharide-elicited-expression-of-proinflammatory-cytokines-in-macrophage-like-hl-60-cells
#2
Hiroshi Kitamura, Takeshi Ishino, Yoshinori Shimamoto, Jun Okabe, Tomomi Miyamoto, Eiki Takahashi, Ichiro Miyoshi
We investigated the regulatory roles of USP2 in mRNA accumulation of proinflammatory cytokines in macrophage-like cells after stimulation with a toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). Human macrophage-like HL-60 cells, mouse macrophage-like J774.1 cells, and mouse peritoneal macrophages demonstrated negative feedback to USP2 mRNA levels after LPS stimulation, suggesting that USP2 plays a significant role in LPS-stimulated macrophages. USP2 knockdown (KD) by short hairpin RNA in HL-60 cells promoted the accumulation of transcripts for 25 of 104 cytokines after LPS stimulation...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/29138251/mitochondrial-inner-membrane-protease-yme1-degrades-outer-membrane-proteins-tom22-and-om45
#3
Xi Wu, Lanlan Li, Hui Jiang
Mitochondria are double-membraned organelles playing essential metabolic and signaling functions. The mitochondrial proteome is under surveillance by two proteolysis systems: the ubiquitin-proteasome system degrades mitochondrial outer-membrane (MOM) proteins, and the AAA proteases maintain the proteostasis of intramitochondrial compartments. We previously identified a Doa1-Cdc48(-Ufd1-Npl4) complex that retrogradely translocates ubiquitinated MOM proteins to the cytoplasm for degradation. In this study, we report the unexpected identification of MOM proteins whose degradation requires the Yme1(-Mgr1-Mgr3)i-AAA protease complex in mitochondrial inner membrane...
November 14, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29131570/identification-and-characterisation-of-dual-inhibitors-of-the-usp25-28-deubiquitinating-enzyme-subfamily
#4
Jonathan D Wrigley, Gerald Gavory, Iain Simpson, Marian Preston, Helen Plant, Jenna Bradley, Anne U Goeppert, Ewelina Rozycka, Gareth Davies, Jarrod Walsh, Andrea Valentine, Keeva McClelland, Krzysztofa Ewa Odrzywol, Jonathan Renshaw, Joanna Boros, Jonathan Tart, Lindsey Leach, Thorsten Nowak, Richard A Ward, Timothy Harrison, David M Andrews
The Ubiquitin Proteasome System is widely postulated to be a new and important field of drug discovery for the future, with the Ubiquitin Specific Proteases (USP) representing one of the more attractive target classes within the area. Many USPs have been linked to critical axes for therapeutic intervention, and the finding that USP28 is required for c-Myc stability suggests that USP28 inhibition may represent a novel approach to target this so far undruggable oncogene. Here we describe the discovery of the first reported inhibitors of USP28, which we demonstrate are able to bind to and inhibit USP28, and whilst displaying a dual activity against the closest homologue USP25, these inhibitors show a high degree of selectivity over other deubiquitinases...
November 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29130109/deubiquitinase-usp9x-promotes-cell-migration-invasion-and-inhibits-apoptosis-of-human-pancreatic-cancer
#5
Li Liu, Dan Yao, Pengbo Zhang, Weichao Ding, Xiuzhong Zhang, Chong Zhang, Shuai Gong, Yi Zhang, Jike Wang, Ting Sun, Zeqiang Ren
Ubiquitin specific peptidase 9, X-linked (USP9X), a significant regulatory protease in protein ubiquitination, has been proven to act as a proto-oncogene in several types of cancers, such as cervix, colon, breast, brain and lung cancers. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to its high invasive and metastatic abilities. Nevertheless, whether USP9X acts as a proto-oncogene or a tumor-suppressor gene in PDAC is controversial and the mechanism of metastasis remains unknown...
December 2017: Oncology Reports
https://www.readbyqxmd.com/read/29117247/a-mobile-loop-near-the-active-site-acts-as-a-switch-between-the-dual-activities-of-a-viral-protease-deubiquitinase
#6
Isabelle Jupin, Maya Ayach, Lucile Jomat, Sonia Fieulaine, Stéphane Bressanelli
The positive-strand RNA virus Turnip yellow mosaic virus (TYMV) encodes an ovarian tumor (OTU)-like protease/deubiquitinase (PRO/DUB) protein domain involved both in proteolytic processing of the viral polyprotein through its PRO activity, and in removal of ubiquitin chains from ubiquitylated substrates through its DUB activity. Here, the crystal structures of TYMV PRO/DUB mutants and molecular dynamics simulations reveal that an idiosyncratic mobile loop participates in reversibly constricting its unusual catalytic site by adopting "open", "intermediate" or "closed" conformations...
November 8, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29101126/induction-of-deubiquitinating-enzyme-usp50-during-erythropoiesis-and-its-potential-role-in-the-regulation-of-ku70-stability
#7
Junting Cai, Jianxin Wei, Valerie Schrott, Jing Zhao, Grant Bullock, Yutong Zhao
Anemia is a very common blood disorder that affects the lives of billions of people worldwide. Anemia is caused by the loss of blood, increased destruction of red blood cells (RBCs), or reduced production of RBCs. Erythropoiesis is the complex process of RBC differentiation and maturation, in which protein degradation plays a crucial role. Protein ubiquitination regulates programmed protein degradation, which can be reversed by deubiquitinating enzymes (DUBs); however, the role of DUBs in erythropoiesis has not been well studied...
November 3, 2017: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
https://www.readbyqxmd.com/read/29093475/hsp90-recognizes-the-n-terminus-of-huntingtin-involved-in-regulation-of-huntingtin-aggregation-by-usp19
#8
Wen-Tian He, Wei Xue, Yong-Guang Gao, Jun-Ye Hong, Hong-Wei Yue, Lei-Lei Jiang, Hong-Yu Hu
Huntington's disease (HD) is caused by aberrant expansion of polyglutamine (polyQ) in the N-terminus of huntingtin (Htt). Our previous study has demonstrated that HSP90 is involved in the triage decision of Htt, but how HSP90 recognizes and regulates Htt remains elusive. We investigated the interaction between HSP90 and the N-terminal fragments of Htt (Htt-N), such as the N-terminal 90-residue fragment (Htt-N90). Our results showed that HSP90 binds to the N-terminal extreme of Htt-N in a sequence just ahead of the polyQ tract...
November 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29091922/characterization-of-the-deubiquitination-activity-and-substrate-specificity-of-the-chicken-ubiquitin-specific-protease-1-usp-associated-factor-1-complex
#9
Hainan Zheng, Mengyun Wang, Chengcheng Zhao, Shanli Wu, Peifeng Yu, Yan Lü, Tiedong Wang, Yongxing Ai
Deubiquitinases (DUBs) are essential regulators of intracellular processes involving ubiquitin (Ub) modification. The human DUB ubiquitin-specific protease 1 (hUSP1) interacts with human USP-associated factor 1 (hUAF1), and helps to regulate processes such as DNA damage repair. Previously, we identified a chicken USP1 homologue (chUSP1) during an investigation into the properties of Marek's disease virus (MDV). However, chUSP1's deubiquitination activity, interaction with chUAF1, and substrate specificity remained unknown...
2017: PloS One
https://www.readbyqxmd.com/read/29079793/site-specific-identification-and-quantitation-of-endogenous-sumo-modifications-under-native-conditions
#10
Ryan J Lumpkin, Hongbo Gu, Yiying Zhu, Marilyn Leonard, Alla S Ahmad, Karl R Clauser, Jesse G Meyer, Eric J Bennett, Elizabeth A Komives
Small ubiquitin-like modifier (SUMO) modification regulates numerous cellular processes. Unlike ubiquitin, detection of endogenous SUMOylated proteins is limited by the lack of naturally occurring protease sites in the C-terminal tail of SUMO proteins. Proteome-wide detection of SUMOylation sites on target proteins typically requires ectopic expression of mutant SUMOs with introduced tryptic sites. Here, we report a method for proteome-wide, site-level detection of endogenous SUMOylation that uses α-lytic protease, WaLP...
October 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29066667/two-sumo-proteases-sumo-protease-related-to-fertility-1-and-2-are-required-for-fertility
#11
Linpo Liu, Ying Jiang, Xiaomei Zhang, Xu Wang, Yanbing Wang, Yuzhen Han, George Coupland, Jing Bo Jin, Iain R Searle, Yongfu Fu, Fulu Chen
In plants, the post-translational modification small ubiquitin-like modifier (SUMO) is involved in regulating several important developmental and cellular processes, including flowering-time control and responses to biotic and abiotic stresses. Here, we report two proteases, SUMO PROTEASE RELATED TO FERTILITY (SPF) 1 and SPF2, that regulate male and female gamete and embryo development and remove SUMO from proteins in vitro and in vivo. spf1 mutants exhibit abnormal floral structures and embryo development, while spf2 mutants exhibit largely a wild type phenotype...
October 24, 2017: Plant Physiology
https://www.readbyqxmd.com/read/29065837/usp7-target-validation-and-drug-discovery-for-cancer-therapy
#12
Jin Zhou, Jinzheng Wang, Chao Chen, Haoliang Yuan, Xiaoan Wen, Hongbin Sun
BACKGROUND: USP7 (ubiquitin specific protease 7, also known as HAUSP) is one of the deubiquitinating enzymes (DUB) that reverse ubiquitination and spare substrate proteins from degradation. METHODS: After a brief introduction of ubiquitin-proteasome system (UPS) and human DUB, this review focuses on the structural and functional complexity of USP7 in tumor development and progression. Afterwards, USP7's physiological regulatory mechanisms and manipulation strategies are elaborated...
October 20, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/29064679/mutation-of-asn-475-in-the-venezuelan-equine-encephalitis-virus-nsp2-cysteine-protease-leads-to-a-self-inhibited-state
#13
Jaimee R Compton, Matthew J Mickey, Xin Hu, Juan J Marugan, Patricia M Legler
The alphaviral nsP2 cysteine protease of the Venezuelan equine encephalitis virus (VEEV) is a validated antiviral drug target. Clan CN proteases contain a cysteine protease domain that is intimately packed with an S-adenosyl-l-methionine-dependent RNA methyltransferase (SAM MTase) domain. Within a cleft formed at the interface of these two domains, the peptide substrate is thought to bind. The nucleophilic cysteine can be found within a conserved motif, (475)NVCWAK(480), which differs from that of papain ((22)CGSCWAFS(29))...
November 9, 2017: Biochemistry
https://www.readbyqxmd.com/read/29061731/the-ubiquitin-specific-protease-usp6-regulates-the-stability-of-the-c-jun-protein
#14
Lisheng Li, Hong Yang, Ting Li, Jinan Feng, Wanze Chen, Lu Ao, Xuying Shi, Yingying Lin, Haoyun Liu, Enrun Zheng, Qiaofa Lin, Jingjing Bu, Yanhua Zeng, Min Zheng, Yan Xu, Zhijun Liao, Jiacheng Lin, Yan He, Dexin Lin
The c-Jun gene encodes a transcription factor that has been implicated in many physiological and pathological processes. c-Jun is a highly unstable protein that is degraded through an ubiquitination/proteasome-dependent mechanism. However, the deubiquitinating enzyme (DUB) that regulates the stability of the c-Jun protein requires further investigation. Here, by screening a DUB expression library, we identified the ubiquitin-specific protease 6 (USP6) and showed that it regulates the stability of the c-Jun protein in a manner depending on its enzyme activity...
October 23, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29060933/sumo-specific-protease-2-mediated-desumoylation-is-required-for-ndrg2-stabilization-in-gastric-cancer-cells
#15
Xiao-Yan Hu, Zhe Liu, Kai-Lin Zhang, Jing Feng, Xiao-Fang Liu, Ling-Yun Wang, Zi-Wei Wang
N-myc downstream regulated gene 2 (NDRG2) is frequently down-regulated in various cancers and functions as a candidate tumor suppressor gene. NDRG2 has been shown to be SUMOylated on the lysine 333 residue, which promoted its ubiquitination and sequentially degradation by the SUMO-targeted ubiquitin E3 ligase RNF4. However, how to regulated NDRG2 deSUMOylation process remains largely unknown. Here, we report that Sentrin/SUMO specific protease (SENP2) was down-regulated in clinic gastric cancer samples and possessed a tumor-suppressive role in gastric cancer...
October 9, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/29056421/structure-guided-development-of-a-potent-and-selective-non-covalent-active-site-inhibitor-of-usp7
#16
Ilaria Lamberto, Xiaoxi Liu, Hyuk-Soo Seo, Nathan J Schauer, Roxana E Iacob, Wanyi Hu, Deepika Das, Tatiana Mikhailova, Ellen L Weisberg, John R Engen, Kenneth C Anderson, Dharminder Chauhan, Sirano Dhe-Paganon, Sara J Buhrlage
Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5-10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies...
September 28, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29045389/molecular-basis-of-usp7-inhibition-by-selective-small-molecule-inhibitors
#17
Andrew P Turnbull, Stephanos Ioannidis, Wojciech W Krajewski, Adan Pinto-Fernandez, Claire Heride, Agnes C L Martin, Louise M Tonkin, Elizabeth C Townsend, Shane M Buker, David R Lancia, Justin A Caravella, Angela V Toms, Thomas M Charlton, Johanna Lahdenranta, Erik Wilker, Bruce C Follows, Nicola J Evans, Lucy Stead, Cristina Alli, Vladislav V Zarayskiy, Adam C Talbot, Alexandre J Buckmelter, Minghua Wang, Crystal L McKinnon, Fabienne Saab, Joanna F McGouran, Hannah Century, Malte Gersch, Marc S Pittman, C Gary Marshall, Tony M Raynham, Mary Simcox, Lorna M D Stewart, Sheila B McLoughlin, Jaime A Escobedo, Kenneth W Bair, Christopher J Dinsmore, Tim R Hammonds, Sunkyu Kim, Sylvie Urbé, Michael J Clague, Benedikt M Kessler, David Komander
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells...
October 26, 2017: Nature
https://www.readbyqxmd.com/read/29045385/usp7-small-molecule-inhibitors-interfere-with-ubiquitin-binding
#18
Lorna Kategaya, Paola Di Lello, Lionel Rougé, Richard Pastor, Kevin R Clark, Jason Drummond, Tracy Kleinheinz, Eva Lin, John-Paul Upton, Sumit Prakash, Johanna Heideker, Mark McCleland, Maria Stella Ritorto, Dario R Alessi, Matthias Trost, Travis W Bainbridge, Michael C M Kwok, Taylur P Ma, Zachary Stiffler, Bradley Brasher, Yinyan Tang, Priyadarshini Jaishankar, Brian R Hearn, Adam R Renslo, Michelle R Arkin, Frederick Cohen, Kebing Yu, Frank Peale, Florian Gnad, Matthew T Chang, Christiaan Klijn, Elizabeth Blackwood, Scott E Martin, William F Forrest, James A Ernst, Chudi Ndubaku, Xiaojing Wang, Maureen H Beresini, Vickie Tsui, Carsten Schwerdtfeger, Robert A Blake, Jeremy Murray, Till Maurer, Ingrid E Wertz
The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival...
October 26, 2017: Nature
https://www.readbyqxmd.com/read/29039560/20-hydroxyeicosatetraenoic-acid-regulates-the-expression-of-nedd4%C3%A2-2-in-kidney-and-liver-through-a-neddylation-modification-pathway
#19
Jianzhu Zhao, Bijun Zhang, Guangrui Lai, Runhong Xu, Guoming Chu, Yanyan Zhao
The present study aimed to test whether 20-hydroxyeicosatetraenoic acid (20‑HETE) affected neddylation modification of E3‑ligase Nedd4‑2 (neural precursor cell expressed, developmentally down‑regulated 4‑like, E3 ubiquitin protein ligase). A cytochrome P450 family 4 subfamily F member 2 (CYP4F2) transgenic mouse model that overproduces 20‑HETE in the kidney and the liver was used in the present study. Transgenic mice with high salt intake exhibited increased activation of Nedd4‑2‑mediated ubiquitin‑proteasome pathway...
December 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29024335/fifty-shades-of-sumo-its-role-in-immunity-and-at-the-fulcrum-of-growth-defense-balance
#20
Vivek Verma, Fenella Crolley, Ari Sadanandom
The sessile nature of plants requires them to cope with an ever changing environment. Effective adaptive responses require sophisticated cellular mechanisms at post-transcriptional and -translational levels. Post-translational modification by Small Ubiquitin-like Modifier (SUMO) proteins is emerging as a key player in these adaptive responses. SUMO conjugation can rapidly change the overall fate of target proteins by altering their stability or interaction with partner proteins or DNA. SUMOylation entails an enzyme cascade that leads to the activation, conjugation and ligation of SUMO to lysine residues of target proteins...
October 10, 2017: Molecular Plant Pathology
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