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https://www.readbyqxmd.com/read/29070670/ifn-%C3%AE-4-attenuates-antiviral-responses-by-enhancing-negative-regulation-of-ifn-signaling
#1
Adeola A Obajemu, Nina Rao, Kari A Dilley, Joselin M Vargas, Faruk Sheikh, Raymond P Donnelly, Reed S Shabman, Eric G Meissner, Ludmila Prokunina-Olsson, Olusegun O Onabajo
Type III IFNs are important mediators of antiviral immunity. IFN-λ4 is a unique type III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-λ4, an antiviral cytokine, are also less likely to clear hepatitis C virus infection. In this study, we searched for unique functional properties of IFN-λ4 that might explain its negative effect on hepatitis C virus clearance. We used fresh primary human hepatocytes (PHHs) treated with recombinant type III IFNs or infected with Sendai virus to model acute viral infection and subsequently validated our findings in HepG2 cell line models...
October 25, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29067635/interferon-regulated-gene-irg-expression-signature-in-a-mouse-model-of-chikungunya-virus-neurovirulence
#2
Sreeja R Nair, Rachy Abraham, Sankar Sundaram, Easwaran Sreekumar
Interferon regulated genes (IRGs) are critical in controlling virus infections. Here, we analyzed the expression profile of IRGs in the brain tissue in a mouse model of chikungunya virus (CHIKV) neurovirulence. Neurovirulence is one of the newer complications identified in disease caused by re-emerging strains of CHIKV, an alphavirus with positive-strand RNA in the Togaviridae family. In microarray analysis, we identified significant upregulation of 269 genes, out of which a predominant percentage (76%) was IRGs...
October 24, 2017: Journal of Neurovirology
https://www.readbyqxmd.com/read/29040650/interferon-alpha-reduces-human-hippocampal-neurogenesis-and-increases-apoptosis-via-activation-of-distinct-stat1-dependent-mechanisms
#3
Alessandra Borsini, Annamaria Cattaneo, Chiara Malpighi, Sandrine Thuret, Neil A Harrison, Patricia A Zunszain, Carmine M Pariante
Background: In humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis. Methods: We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis...
October 10, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29040318/rapid-reversal-of-innate-immune-dysregulation-in-blood-of-patients-and-livers-of-humanized-mice-with-hcv-following-daa-therapy
#4
Matthew A Burchill, Justin A Roby, Nanette Crochet, Megan Wind-Rotolo, Amy E Stone, Michael G Edwards, Rachael J Dran, Michael S Kriss, Michael Gale, Hugo R Rosen
RESULTS: First, in patients receiving two different combinations of DAAs, we found that DAAs induced not only rapid viral clearance, but also a re-setting of antiviral immune responses in the peripheral blood. Specifically, we see a rapid decline in the expression of genes associated with chronic IFN stimulation (IFIT3, USP18, IFIT1) as well as a rapid decline in genes associated with inflammation (IL1β, CXCL10, CXCL11) in the peripheral blood that precedes the complete removal of virus from the blood...
2017: PloS One
https://www.readbyqxmd.com/read/28900038/socs1-is-an-inducible-negative-regulator-of-interferon-%C3%AE-ifn-%C3%AE-induced-gene-expression-in-vivo
#5
Tanja Blumer, Mairene Coto-Llerena, Francois H T Duong, Markus H Heim
Type I (α and β) and type III (λ) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor κB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-αs and IFN-λs. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis...
October 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28881486/how-usp18-deals-with-isg15-modified-proteins-structural-basis-for-the-specificity-of-the-protease
#6
REVIEW
Anja Basters, Klaus-Peter Knobeloch, Günter Fritz
The Ubiquitin-specific protease 18 (USP18) has two major functions: (i) it is a highly specific protease that cleaves the ubiquitin-like modifier ISG15 (interferon stimulated gene 15 kDa) from proteins, and (ii) independent from its enzymatic activity USP18 interacts with the type I interferon receptor and shuts off downstream signaling. The structures of USP18 and a USP18-ISG15 complex revealed the molecular basis of the unique specificity of the protease and might shed some light into its interaction with the interferon receptor...
September 7, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28825532/replication-of-a-low-pathogenic-avian-influenza-virus-is-enhanced-by-chicken-ubiquitin-specific-protease-18
#7
Taichiro Tanikawa, Yuko Uchida, Takehiko Saito
Previous research revealed the induction of chicken USP18 (chUSP18) in the lungs of chickens infected with highly pathogenic avian influenza viruses (HPAIVs). This activity was correlated with the degree of pathogenicity of the viruses to chickens. As mammalian ubiquitin-specific protease (USP18) is known to remove type I interferon (IFN I)-inducible ubiquitin-like molecules from conjugated proteins and block IFN I signalling, we explored the function of the chicken homologue of USP18 during avian influenza virus infection...
September 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28718215/usp18-protects-against-hepatic-steatosis-and-insulin-resistance-via-its-dub-activity
#8
Shimin An, Ling-Ping Zhao, Li-Jun Shen, Siyuan Wang, Kuo Zhang, Yu Qi, Jilin Zheng, Xiao-Jing Zhang, Xue-Yong Zhu, Rong Bao, Ling Yang, Yue-Xin Lu, Zhi-Gang She, Yi-Da Tang
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we first report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating (DUB) enzyme family, plays regulatory roles in NAFLD progression. The expression of USP18 was down-regulated in the livers of non-alcoholic steatohepatitis (NASH) patients and high-fat diet (HFD) induced or genetically obese mice...
July 17, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28709980/downregulation-of-usp18-inhibits-growth-and-induces-apoptosis-in-hepatitis-b-virus-related-hepatocellular-carcinoma-cells-by-suppressing-bcl2l1
#9
Jing Cai, Tiande Liu, Xiaoliu Jiang, Changkuo Guo, Anwen Liu, Xinlan Xiao
Ubiquitin-specific peptidase 18 (USP18) is closely related with hepatitis B virus (HBV), which has been involved in tumourigenesis. However, there has been little research into the role of USP18 on the progression of hepatocellular carcinoma (HCC), especially in HBV-related HCC. In present study, we found that USP18 expression was aberrantly elevated in HCC tissues than adjacent non-tumour tissues. Importantly, USP18 expression was higher in HBV-related HCC cell lines (HepG2.2.15 and Hep3B) than HBV-unrelated HCC cell lines...
September 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28698279/zika-virus-persistently-infects-and-is-basolaterally-released-from-primary-human-brain-microvascular-endothelial-cells
#10
Megan C Mladinich, John Schwedes, Erich R Mackow
Zika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB) to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC) lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons...
July 11, 2017: MBio
https://www.readbyqxmd.com/read/28630501/ifn-%C3%AE-4-potently-blocks-ifn-%C3%AE-signalling-by-isg15-and-usp18-in-hepatitis-c-virus-infection
#11
Pil Soo Sung, Seon-Hui Hong, Jae-Hee Chung, Sojeong Kim, Su-Hyung Park, Ho Min Kim, Seung Kew Yoon, Eui-Cheol Shin
Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-α-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-ΔG genotype, which encodes functional IFN-λ4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-λ4 in HCV-infected hepatocytes and their association with responsiveness to IFN-α. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-λ4 expression and IFN-α responsiveness...
June 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28605413/acute-bovine-viral-diarrhea-virus-infection-inhibits-expression-of-interferon-tau-stimulated-genes-in-bovine-endometrium
#12
Zhangrui Cheng, Latta Chauhan, Amy Teresa Barry, Ayimuguli Abudureyimu, Chike F Oguejiofor, Xing Chen, D Claire Wathes
Bovine viral diarrhea virus (BVDV) can evade host detection by downregulation of interferon signaling pathways. Infection of cows with noncytopathic (ncp) BVDV can cause early embryonic mortality. Upregulation of type I interferon stimulated genes (ISGs) by blastocyst-secreted interferon tau (IFNT) is a crucial component of the maternal recognition of pregnancy (MRP) in ruminants. This study investigated the potential of acute BVDV infection to disrupt MRP by modulating endometrial ISG expression. Endometrial cells from 10 BVDV-free cows were cultured and treated with 0 or 100 ng/ml IFNT for 24 h in the absence or presence of ncpBVDV infection to yield four treatment groups: CONT, ncpBVDV, IFNT, or ncpBVDV+IFNT...
June 1, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28557172/deubiquitinase-usp18-prevents-cellular-apoptosis-from-oxidative-stress-in-liver-cells
#13
Keng Po Lai, Angela Hoi Yan Cheung, William Ka Fai Tse
Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate their activity and stability. They play different cellular functions such as cell cycle regulation, DNA repair, and early embryogenesis. Additionally, studies have demonstrated that some DUBs are the signaling targets of cellular stress such as oxidative stress. Reactive oxygen species are generated during normal mitochondrial oxidative metabolism and proper cellular mechanism could protect the cell from the oxidative stress...
May 30, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28540600/microglial-interferon-signaling-and-white-matter
#14
Ashley McDonough, Richard V Lee, Jonathan R Weinstein
Microglia, the resident immune cells of the CNS, are primary regulators of the neuroimmune response to injury. Type I interferons (IFNs), including the IFNαs and IFNβ, are key cytokines in the innate immune system. Their activity is implicated in the regulation of microglial function both during development and in response to neuroinflammation, ischemia, and neurodegeneration. Data from numerous studies in multiple sclerosis (MS) and stroke suggest that type I IFNs can modulate the microglial phenotype, influence the overall neuroimmune milieu, regulate phagocytosis, and affect blood-brain barrier integrity...
September 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28519900/type-i-interferon-pathway-in-cns-homeostasis-and-neurological-disorders
#15
REVIEW
Thomas Blank, Marco Prinz
Type I interferons (IFNs), IFN-α and IFN-β, represent the major effector cytokines of the host immune response against viruses and other intracellular pathogens. These cytokines are produced via activation of numerous pattern recognition receptors, including the Toll-like receptor signaling network, retinoic acid-inducible gene-1 (RIG-1), melanoma differentiation-associated protein-5 (MDA-5) and interferon gamma-inducible protein-16 (IFI-16). Whilst the contribution of type I IFNs to peripheral immunity is well documented, they can also be produced by almost every cell in the central nervous system (CNS)...
September 2017: Glia
https://www.readbyqxmd.com/read/28432122/dual-regulation-of-stat1-and-stat3-by-the-tumor-suppressor-protein-pml-contributes-to-interferon-%C3%AE-mediated-inhibition-of-angiogenesis
#16
COMPARATIVE STUDY
Kuo-Sheng Hsu, Xuan Zhao, Xiwen Cheng, Dongyin Guan, Ganapati H Mahabeleshwar, Yu Liu, Ernest Borden, Mukesh K Jain, Hung-Ying Kao
IFNs are effective in inhibiting angiogenesis in preclinical models and in treating several angioproliferative disorders. However, the detailed mechanisms of IFNα-mediated anti-angiogenesis are not completely understood. Stat1/2/3 and PML are IFNα downstream effectors and are pivotal regulators of angiogenesis. Here, we investigated PML's role in the regulation of Stat1/2/3 activity. In Pml knock-out (KO) mice, ablation of Pml largely reduces IFNα angiostatic ability in Matrigel plug assays. This suggested an essential role for PML in IFNα's anti-angiogenic function...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28369997/gene-expression-profile-after-knockdown-of-usp18-in-hepg2-2-15-cells
#17
Lin Li, Qing-Song Lei, Ling-Na Kong, Shu-Jun Zhang, Bo Qin
In our previous work, we found that the expression of ubiquitin-specific protease 18 (USP18), also known as UBP43, is associated with the efficiency of interferon alpha (IFN-α) treatment in patients with chronic hepatitis B (CHB). To elucidate the influence of USP18 on hepatitis B virus (HBV) replication and the mechanism of this activity, we silenced USP18 by introducing short hairpin RNA (shRNA) into Hepg2.2.15 cells. To identify the changed genes and pathways in Hepg2.2.15-shRNA-USP18 cells, we performed a microarray gene expression analysis to compare the Hepg2...
March 31, 2017: Journal of Medical Virology
https://www.readbyqxmd.com/read/28242811/deubiquitinase-usp18-loss-mislocalizes-and-destabilizes-kras-in-lung-cancer
#18
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 IFN-stimulated gene 15 (ISG15) deubiquitinase (DUB) USP18 as having antineoplastic 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...
July 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28165510/stat2-is-an-essential-adaptor-in-usp18-mediated-suppression-of-type-i-interferon-signaling
#19
Kei-Ichiro Arimoto, Sara Löchte, Samuel A Stoner, Christoph Burkart, Yue Zhang, Sayuri Miyauchi, Stephan Wilmes, Jun-Bao Fan, Jürgen J Heinisch, Zhi Li, Ming Yan, Sandra Pellegrini, Frédéric Colland, Jacob Piehler, Dong-Er Zhang
Type I interferons (IFNs) are multifunctional cytokines that regulate immune responses and cellular functions but also can have detrimental effects on human health. A tight regulatory network therefore controls IFN signaling, which in turn may interfere with medical interventions. The JAK-STAT signaling pathway transmits the IFN extracellular signal to the nucleus, thus resulting in alterations in gene expression. STAT2 is a well-known essential and specific positive effector of type I IFN signaling. Here, we report that STAT2 is also a previously unrecognized, crucial component of the USP18-mediated negative-feedback control in both human and mouse cells...
March 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28165509/structural-basis-of-the-specificity-of-usp18-toward-isg15
#20
Anja Basters, Paul P Geurink, Annika Röcker, Katharina F Witting, Roya Tadayon, Sandra Hess, Marta S Semrau, Paola Storici, Huib Ovaa, Klaus-Peter Knobeloch, Günter Fritz
Protein modification by ubiquitin and ubiquitin-like modifiers (Ubls) is counteracted by ubiquitin proteases and Ubl proteases, collectively termed DUBs. In contrast to other proteases of the ubiquitin-specific protease (USP) family, USP18 shows no reactivity toward ubiquitin but specifically deconjugates the interferon-induced Ubl ISG15. To identify the molecular determinants of this specificity, we solved the crystal structures of mouse USP18 alone and in complex with mouse ISG15. USP18 was crystallized in an open and a closed conformation, thus revealing high flexibility of the enzyme...
March 2017: Nature Structural & Molecular Biology
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