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https://www.readbyqxmd.com/read/28718215/usp18-protects-against-hepatic-steatosis-and-insulin-resistance-via-its-dub-activity
#1
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
#2
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...
July 11, 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
#3
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
#4
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-diarrhoea-virus-infection-inhibits-expression-of-interferon-tau-stimulated-genes-in-bovine-endometrium
#5
Zhangrui Cheng, Latta Chauhan, Amy Teresa Barry, Ayimuguli Abudureyimu, Chike F Oguejiofor, Xing Chen, D Claire Wathes
Bovine viral diarrhoea virus (BVDV) can evade host detection by down-regulation of interferon signalling pathways. Infection of cows with non-cytopathic (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 4 treatment groups: CONT, ncpBVDV, IFNT or ncpBVDV+IFNT...
June 12, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28557172/deubiquitinase-usp18-prevents-cellular-apoptosis-from-oxidative-stress-in-liver-cells
#6
Keng Po Lai, Angela Hoi Yan Cheung, William Ka Fai Tse
Deubiquitinases (DUBs) de-conjugate 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
#7
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...
May 25, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28519900/type-i-interferon-pathway-in-cns-homeostasis-and-neurological-disorders
#8
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
#9
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
#10
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
#11
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...
February 27, 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
#12
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
#13
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
https://www.readbyqxmd.com/read/27980214/the-isg15-specific-protease-usp18-regulates-stability-of-pten
#14
Lisa Maria Mustachio, Masanori Kawakami, Yun Lu, Jaime Rodriguez-Canales, Barbara Mino, Carmen Behrens, Ignacio Wistuba, Neus Bota-Rabassedas, Jun Yu, J Jack Lee, Jason Roszik, Lin Zheng, Xi Liu, Sarah J Freemantle, Ethan Dmitrovsky
The ubiquitin-like modifier interferon-stimulated gene 15 (ISG15) is implicated in both oncogenic and tumor suppressive programs. Yet, few ISGylation substrates are known and functionally validated in cancer biology. We previously found specific oncoproteins were substrates of ISGylation and were stabilized by the ISG15-specific deubiquitinase (DUB) ubiquitin specific peptidase 18 (USP18). Using reverse-phase protein arrays (RPPAs), this study reports that engineered loss of the DUB USP18 destabilized the tumor suppressor protein phosphatase and tensin homologue (PTEN) in both murine and human lung cancer cell lines...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27923569/gender-differences-of-b-cell-signature-related-to-estrogen-induced-ifi44l-baff-in-systemic-lupus-erythematosus
#15
Hongye Fan, Guangfeng Zhao, Deshan Ren, Fei Liu, Guanjun Dong, Yayi Hou
Systemic lupus erythematosus (SLE) possesses a gender-dependent incidence characterized by a male/female ratio 1:9. B-cell, a vital part of the immune system, plays an important role in pathogenesis of SLE. Thus, we hypothesize that gender differences of B cells may exist in SLE and relate to the onset and the progression of SLE. Here, we showed that the genes expression pattern is similar between healthy female and male. However, SLE female and SLE male showed more upregulated genes, in which the trendline of SLE male is higher than that of SLE female...
December 5, 2016: Immunology Letters
https://www.readbyqxmd.com/read/27882925/isgylation-controls-exosome-secretion-by-promoting-lysosomal-degradation-of-mvb-proteins
#16
Carolina Villarroya-Beltri, Francesc Baixauli, María Mittelbrunn, Irene Fernández-Delgado, Daniel Torralba, Olga Moreno-Gonzalo, Sara Baldanta, Carlos Enrich, Susana Guerra, Francisco Sánchez-Madrid
Exosomes are vesicles secreted to the extracellular environment through fusion with the plasma membrane of specific endosomes called multivesicular bodies (MVB) and mediate cell-to-cell communication in many biological processes. Posttranslational modifications are involved in the sorting of specific proteins into exosomes. Here we identify ISGylation as a ubiquitin-like modification that controls exosome release. ISGylation induction decreases MVB numbers and impairs exosome secretion. Using ISG15-knockout mice and mice expressing the enzymatically inactive form of the de-ISGylase USP18, we demonstrate in vitro and in vivo that ISG15 conjugation regulates exosome secretion...
November 24, 2016: Nature Communications
https://www.readbyqxmd.com/read/27809302/multiple-functions-of-usp18
#17
REVIEW
Nadine Honke, Namir Shaabani, Dong-Er Zhang, Cornelia Hardt, Karl S Lang
Since the discovery of the ubiquitin system and the description of its important role in the degradation of proteins, many studies have shown the importance of ubiquitin-specific peptidases (USPs). One special member of this family is the USP18 protein (formerly UBP43). In the past two decades, several functions of USP18 have been discovered: this protein is not only an isopeptidase but also a potent inhibitor of interferon signaling. Therefore, USP18 functions as 'a' maestro of many biological pathways in various cell types...
November 3, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27801882/usp18-recruits-usp20-to-promote-innate-antiviral-response-through-deubiquitinating-sting-mita
#18
Man Zhang, Meng-Xin Zhang, Qiang Zhang, Gao-Feng Zhu, Lei Yuan, Dong-Er Zhang, Qiyun Zhu, Jing Yao, Hong-Bing Shu, Bo Zhong
STING (also known as MITA) mediates the innate antiviral signaling and ubiquitination of STING is key to its function. However, the deubiquitination process of STING is unclear. Here we report that USP18 recruits USP20 to deconjugate K48-linked ubiquitination chains from STING and promotes the stability of STING and the expression of type I IFNs and proinflammatory cytokines after DNA virus infection. USP18 deficiency or knockdown of USP20 resulted in enhanced K48-linked ubiquitination and accelerated degradation of STING, and impaired activation of IRF3 and NF-κB as well as induction of downstream genes after infection with DNA virus HSV-1 or transfection of various DNA ligands...
December 2016: Cell Research
https://www.readbyqxmd.com/read/27716962/acetaldehyde-disrupts-interferon-alpha-signaling-in-hepatitis-c-virus-infected-liver-cells-by-up-regulating-usp18
#19
Murali Ganesan, Larisa Y Poluektova, Dean J Tuma, Kusum K Kharbanda, Natalia A Osna
BACKGROUND: Alcohol consumption exacerbates the pathogenesis of hepatitis C virus (HCV) infection and worsens disease outcomes. The exact reasons are not clear yet, but they might be partially attributed to the ability of alcohol to further suppress the innate immunity. Innate immunity is known to be already decreased by HCV in liver cells. METHODS: In this study, we aimed to explore the mechanisms of how alcohol metabolism dysregulates IFNα signaling (STAT1 phosphorylation) in HCV(+) hepatoma cells...
November 2016: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/27659523/interferon-stimulated-gene-15-induces-cancer-cell-death-by-suppressing-the-nf-%C3%AE%C2%BAb-signaling-pathway
#20
Hongwu Mao, Man Wang, Biyin Cao, Haibin Zhou, Zubin Zhang, Xinliang Mao
Interferon-stimulated gene 15 (ISG15) is an important cytokine that has been reported in carcinogenesis. However, we found that ISG15 and de-ISGylase USP18 were induced by several anti-cancer agents, which was confirmed by both RT-PCR and immunoblotting assays. Further studies demonstrated that ectopic ISG15 and USP18 inhibited proliferation of myeloma, leukemia and cervical cancer cells. More importantly, ISG15 and USP18 induced cancer cell apoptosis. This finding was confirmed in a cervical xenograft model in which cervical cancer growth was suppressed by lentiviral ISG15...
October 25, 2016: Oncotarget
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