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Ye Ji Kim, Eui Tae Kim, Young-Eui Kim, Myoung Kyu Lee, Ki Mun Kwon, Keun Il Kim, Thomas Stamminger, Jin-Hyun Ahn
Interferon-stimulated gene 15 (ISG15) encodes an ubiquitin-like protein that covalently conjugates protein. Protein modification by ISG15 (ISGylation) is known to inhibit the replication of many viruses. However, studies on the viral targets and viral strategies to regulate ISGylation-mediated antiviral responses are limited. In this study, we show that human cytomegalovirus (HCMV) replication is inhibited by ISGylation, but the virus has evolved multiple countermeasures. HCMV-induced ISG15 expression was mitigated by IE1, a viral inhibitor of interferon signaling, however, ISGylation was still strongly upregulated during virus infection...
August 2016: PLoS Pathogens
Lin Li, Qing-Song Lei, Shu-Jun Zhang, Ling-Na Kong, Bo Qin
Ubiquitin-specific protease 18 (USP18, also known as UBP43) has both interferon stimulated gene 15 (ISG15) dependent and ISG15-independent functions. By silencing the expression of USP18 in HepG2.2.15 cells, we studied the effect of USP18 on the anti-HBV activity of IFN-F and demonstrated that knockdown of USP18 significantly Inhibited the HBV expression and increased the expression of ISGs. Levels of hepatitis B virus surface antigen (HBsAg), hepatitis B virus e antigen (HBeAg), HBV DNA and intracellular hepatitis B virus core antigen (HBcAg) were dramatically decreased with or without treatment of indicated dose of IFN-F...
2016: PloS One
Hwa Young Yim, Cheolkyu Park, Yong Deok Lee, Kei-Ichiro Arimoto, Raok Jeon, Sung Hee Baek, Dong-Er Zhang, Hong-Hee Kim, Keun Il Kim
A balance between bone formation and bone resorption is critical for the maintenance of bone mass. In many pathological conditions, including chronic inflammation, uncontrolled activation of osteoclast differentiation often causes excessive bone resorption that results in osteoporosis. In this study, we identified the osteopenia phenotype of mice lacking Usp18 (also called Ubp43), which is a deISGylating enzyme and is known as a negative regulator of type I IFN signaling. The expression of Usp18 was induced in preosteoclasts upon receptor activator of NF-κB ligand (RANKL) treatment...
May 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Rafael Fernandez-Botran, Swati Joshi-Barve, Smita Ghare, Shirish Barve, Mary Young, Michael Plankey, Jose Bordon
The role of host response-related factors in the fast progression of liver disease in individuals co-infected with HIV and HCV viruses remains poorly understood. This study compared patterns of cytokines, caspase-1 activation, endotoxin exposure in plasma as well as interferon signaling in peripheral blood mononuclear cells from HIV/HCV co-infected (HIV(+)/HCV(+)), HCV mono-infected (HIV(-)/HCV(+)), HIV mono-infected (HIV(+)/HCV(-)) female patients and HIV- and HCV-uninfected women (HIV(-)/HCV(-)) who had enrolled in the Women's Interagency HIV Study (WIHS)...
November 2014: Journal of Interferon & Cytokine Research
Jung Mi Park, Seung Wook Yang, Kyung Ryun Yu, Seung Hyun Ka, Seong Won Lee, Jae Hong Seol, Young Joo Jeon, Chin Ha Chung
In response to DNA damage, PCNA is mono-ubiquitinated and triggers translesion DNA synthesis (TLS) by recruiting polymerase-η. However, it remained unknown how error-prone TLS is turned off after DNA lesion bypass to prevent mutagenesis. Here we showed that ISG15 modification (ISGylation) of PCNA plays a key role in TLS termination. Upon UV irradiation, EFP, an ISG15 E3 ligase, bound to mono-ubiquitinated PCNA and promoted its ISGylation. ISGylated PCNA then tethered USP10 for deubiquitination and in turn the release of polymerase-η from PCNA...
May 22, 2014: Molecular Cell
Punsiri M Colonne, Abha Sahni, Sanjeev K Sahni
Rickettsia conorii, the causative agent of Mediterranean spotted fever, preferentially infects human microvascular endothelium and activates pro-inflammatory innate immune responses as evidenced by enhanced expression and secretion of cytokines and chemokines. Our recent studies reveal that human microvascular endothelial cells (HMECs) infected with R. conorii also launch 'antiviral' host defence mechanisms typically governed by type I interferons. To summarize, infected HMECs secrete IFN-β to activate STAT1 in an autocrine/paracrine manner and display increased expression of IFN-stimulated genes, for example ISG15, which in turn activate innate responses to interfere with intracellular replication of rickettsiae...
July 2013: Journal of Medical Microbiology
Anja Basters, Lars Ketscher, Elke Deuerling, Christoph Arkona, Jörg Rademann, Klaus-Peter Knobeloch, Günter Fritz
BACKGROUND: Covalent linkage of the ubiquitin-like protein ISG15 interferes with viral infection and USP18 is the major protease which specifically removes ISG15 from target proteins. Thus, boosting ISG15 modification by protease inhibition of USP18 might represent a new strategy to interfere with viral replication. However, so far no heterologous expression system was available to yield sufficient amounts of catalytically active protein for high-throughput based inhibitor screens. RESULTS: High-level heterologous expression of USP18 was achieved by applying a chaperone-based fusion system in E...
2012: BMC Biotechnology
Yongli Guo, Fadzai Chinyengetere, Andrey V Dolinko, Alexandra Lopez-Aguiar, Yun Lu, Fabrizio Galimberti, Tian Ma, Qing Feng, David Sekula, Sarah J Freemantle, Angeline S Andrew, Vincent Memoli, Ethan Dmitrovsky
New pharmacologic targets are needed for lung cancer. One candidate pathway to target is composed of the E1-like ubiquitin-activating enzyme (UBE1L) that associates with interferon-stimulated gene 15 (ISG15), which complexes with and destabilizes cyclin D1. Ubiquitin protease 43 (UBP43/USP18) removes ISG15 from conjugated proteins. This study reports that gain of UBP43 stabilized cyclin D1, but not other D-type cyclins or cyclin E. This depended on UBP43 enzymatic activity; an enzymatically inactive UBP43 did not affect cyclin D1 stability...
September 2012: Molecular Cancer Therapeutics
Hwa Young Yim, Young Yang, Jong-Seok Lim, Myeong Seok Lee, Dong-Er Zhang, Keun Il Kim
UBP43 (also known as USP18) plays a role in the negative regulation of interferon-α/β signaling, and bone marrow cells in Ubp43-deficient mice exhibited hypersensitivity to interferon-α/β-mediated apoptosis. Here, we show that the mitochondrial apoptotic pathway and reactive oxygen species are major contributors to the elevated interferon-α/β-mediated apoptosis in Ubp43-deficient mouse bone marrow cells and in UBP43-knockdown THP-1 cells. Furthermore, TRAIL and FASL, which were proposed as apoptosis inducers upon interferon-α/β treatment in UBP43-knockdown adherent cancer cells, did not cause apoptosis in these hematopoietic cells...
June 29, 2012: Biochemical and Biophysical Research Communications
Punsiri M Colonne, Abha Sahni, Sanjeev K Sahni
Rickettsia conorii, an obligate intracellular bacterium and the causative agent of Mediterranean spotted fever, preferentially infects microvascular endothelial cells of the mammalian hosts leading to onset of innate immune responses, characterized by the activation of intracellular signaling mechanisms, release of pro-inflammatory cytokines and chemokines, and killing of intracellular rickettsiae. Our recent studies have shown that interferon (IFN)-β, a cytokine traditionally considered to be involved in antiviral immunity, plays an important role in the autocrine/paracrine regulation of host defense mechanisms and control of R...
December 9, 2011: Biochemical and Biophysical Research Communications
Jason E Duex, Laurey Comeau, Alexander Sorkin, Benjamin Purow, Benjamin Kefas
Epidermal growth factor receptor (EGFR) is involved in development and progression of many human cancers. We have previously demonstrated that the ubiquitin-specific peptidase Usp18 (Ubp43) is a potent regulator of EGFR protein expression. Here we report that the 3'-untranslated region (3'-UTR) of the EGFR message modulates RNA translation following cell treatment with Usp18 siRNA, suggesting microRNA as a possible mediator. Given earlier evidence of EGFR regulation by the microRNA miR-7, we assessed whether miR-7 mediates Usp18 siRNA effects...
July 15, 2011: Journal of Biological Chemistry
A Pierangeli, A M Degener, M L Ferreri, E Riva, B Rizzo, O Turriziani, S Luciani, C Scagnolari, G Antonelli
The aim of this study is to monitor type I interferon (IFN) activation in the cervical mucosa of Human Papillomavirus (HPV)-infected and uninfected women attending a routine gynaecologic clinic. The expression of three IFN-induced genes (MxA coding for human Mixovirus resistance protein A, ISG15 Interferon Stimulated Gene coding for a 15 kDa ubiquitin-like protein and UBP43 coding for the ISG15 isopeptidase) was determined as the mRNA copy number in cervical cells, normalized to the mRNA ones of the beta-glucuronidase gene...
January 2011: International Journal of Immunopathology and Pharmacology
Dongxian Zhang, Dong-Er Zhang
Interferon-stimulated gene 15 (ISG15) is one of the most upregulated genes upon Type I interferon treatment or pathogen infection. Its 17  kDa protein product, ISG15, was the first ubiquitin-like modifier identified, and is similar to a ubiquitin linear dimer. As ISG15 modifies proteins in a similar manner to ubiquitylation, protein conjugation by ISG15 is termed ISGylation. Some of the primary enzymes that promote ISGylation are also involved in ubiquitin conjugation. The process to remove ISG15 from its conjugated proteins, termed de-ISGylation, is performed by a cellular ISG15-specific protease, ubiquitin-specific proteases with molecular mass 43 kDa (UBP43)/ubiquitin-specific proteases 18...
January 2011: Journal of Interferon & Cytokine Research
Yongli Guo, Andrey V Dolinko, Fadzai Chinyengetere, Bruce Stanton, Jennifer M Bomberger, Eugene Demidenko, Da-Cheng Zhou, Robert Gallagher, Tian Ma, Fabrizio Galimberti, Xi Liu, David Sekula, Sarah Freemantle, Ethan Dmitrovsky
More effective treatments for acute promyelocytic leukemia (APL) are needed. APL cell treatment with all-trans-retinoic acid (RA) degrades the chimeric, dominant-negative-acting transcription factor promyelocytic leukemia gene (PML)/RARα, which is generated in APL by chromosomal translocation. The E1-like ubiquitin-activating enzyme (UBE1L) associates with interferon-stimulated gene ISG15 that binds and represses PML/RARα protein. Ubiquitin protease UBP43/USP18 removes ISG15 from conjugated proteins. In this study, we explored how RA regulates UBP43 expression and the effects of UBP43 on PML/RARα stability and APL growth, apoptosis, or differentiation...
December 1, 2010: Cancer Research
Ryan L Ashley, Luiz E Henkes, Gerrit J Bouma, James K Pru, Thomas R Hansen
The ubiquitin homolog interferon stimulated gene 15 (ISG15) is up-regulated in the endometrium in response to pregnancy in primates, ruminants, pigs, and mice. ISG15 covalently attaches to intracellular proteins (isgylation) and regulates numerous intracellular responses. We hypothesized that ISG15 depletion (Isg15(-/-)) alters decidual tissue gene expression and that IL-1beta induces ISG15 expression and isgylation in cultured murine decidual explants and human uterine fibroblasts (HuFs). After studying the reproductive phenotype, contrary to earlier reports, up to 50% of the fetuses die between 7...
September 2010: Endocrinology
Magdalena Sarasin-Filipowicz, Xueya Wang, Ming Yan, Francois H T Duong, Valeria Poli, Douglas J Hilton, Dong-Er Zhang, Markus H Heim
Recombinant alpha interferon (IFN-alpha) is used for the treatment of viral hepatitis and some forms of cancer. During these therapies IFN-alpha is injected once daily or every second day for several months. Recently, the long-acting pegylated IFN-alpha (pegIFN-alpha) has replaced standard IFN-alpha in therapies of chronic hepatitis C because it is more effective, supposedly by inducing a long-lasting activation of IFN signaling pathways. IFN signaling in cultured cells, however, becomes refractory within hours, and little is known about the pharmacodynamic effects of continuously high IFN-alpha serum concentrations...
September 2009: Molecular and Cellular Biology
Ingrid K Ruf, Jennifer L Houmani, Jeffery T Sample
Epstein-Barr virus (EBV) persists as a life-long latent infection within memory B cells, but how EBV may circumvent the innate immune response within this virus reservoir is unclear. Recent studies suggest that the latency-associated non-coding RNAs of EBV may actually induce type I (antiviral) interferon production, raising the question of how EBV counters the negative consequences this is likely to have on viral persistence. We addressed this by examining the type I interferon response in Burkitt lymphoma (BL) cell lines, the only in vitro model of the restricted program of EBV latency-gene expression in persistently infected B cells in vivo...
2009: PloS One
Tahar Ait-Ali, Alison W Wilson, Heather Finlayson, Wilfrid Carré, Sreenivasa Chakravarthy Ramaiahgari, David G Westcott, Martin Waterfall, Jean-Pierre Frossard, Kwang-Hyun Baek, Trevor W Drew, Stephen C Bishop, Alan L Archibald
Emerging evidence places deubiquitylation at the core of a multitude of regulatory processes, ranging from cell growth to innate immune response and health, such as cancer, degenerative and infectious diseases. Little is known about deubiquitylation in pig and arterivirus infection. This report provides information on the biochemical and functional role of the porcine USP18 during innate immune response to the porcine respiratory and reproductive syndrome virus (PRRSV). We have shown that UBP gene is the ortholog of the murine USP18 (Ubp43) gene and the human ubiquitin specific protease 18 (USP18) gene and encodes a biochemically functional de-ubiquitin enzyme which inhibits signalling pathways that lead to IFN-stimulating response element (ISRE) promotor regulation...
June 15, 2009: Gene
Hauke Schmidt, Jenni Raasch, Doron Merkler, Florian Klinker, Sandra Krauss, Wolfgang Brück, Marco Prinz
The type I interferons, interferon-beta and alpha (IFN-beta, IFN-alpha), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-beta as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated...
April 2009: Experimental Neurology
Qing Feng, David Sekula, Yongli Guo, Xi Liu, Candice C Black, Fabrizio Galimberti, Sumit J Shah, Lorenzo F Sempere, Vincent Memoli, Jesper B Andersen, Bret A Hassel, Konstantin Dragnev, Ethan Dmitrovsky
UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation...
December 2008: Molecular Cancer Therapeutics
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