DOCSLIB.ORG

Type I IFN Signaling Infection by Up-Regulating Typhimurium

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Type I IFN Signaling Infection by Up-Regulating Typhimurium Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling This information is current as of September 24, 2021. Keun Il Kim, Oxana A. Malakhova, Kasper Hoebe, Ming Yan, Bruce Beutler and Dong-Er Zhang J Immunol 2005; 175:847-854; ; doi: 10.4049/jimmunol.175.2.847 http://www.jimmunol.org/content/175/2/847 Downloaded from References This article cites 45 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/175/2/847.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Enhanced Antibacterial Potential in UBP43-Deficient Mice against Salmonella typhimurium Infection by Up-Regulating Type I IFN Signaling1 Keun Il Kim,2* Oxana A. Malakhova,* Kasper Hoebe,† Ming Yan,* Bruce Beutler,† and Dong-Er Zhang3* ISG15 is an IFN-inducible ubiquitin-like protein and its expression and conjugation to target proteins are dramatically induced upon viral or bacterial infection. We have generated a UBP43 knockout mouse model that is lacking an ISG15-specific isopeptidase to study the biological role of the protein ISGylation system. We report that UBP43-deficient mice are hypersensitive to LPS- induced lethality and that TIR domain-containing adapter inducing IFN-␤ 3 IFN regulatory factor 3 3 type I IFN is the major ؊/؊ axis to induce protein ISGylation and UBP43 expression in macrophages upon LPS treatment. In ubp43 macrophages, upon Downloaded from LPS treatment we detected increased expression of IFN-stimulated genes, including genes for several cytokines and chemokines involved in the innate immune response. The ubp43؊/؊ mice were able to restrict the growth of Salmonella typhimurium more efficiently than wild-type mice. These results clearly demonstrate two aspects of IFN-signaling, a beneficial effect against pathogens but a detriment to the body without strict control. The Journal of Immunology, 2005, 175: 847–854. nterferons are well-known cytokines that play pivotal roles in ISG15 conjugation process ISGylation follows an analogous http://www.jimmunol.org/ antiviral, antibacterial, cell growth, differentiation, and anti- mechanism to other ubiquitin-like protein modifications (8–10). I tumor responses (1, 2). IFNs are also considered as signals However, the ISGylation system is unique among ubiquitin-like for modulating innate and adaptive immunity (3). Type I IFNs protein systems. The expression of ISG15 and currently known induce several hundred IFN-stimulated genes (ISGs),4 including enzymes for ISGylation and deISGylation are all highly induced cytokine genes, through the Jak/Stat signaling pathway (4). It has by type I IFN. Furthermore, the ISGylation system has been de- been known that Jak/Stat signaling is tightly regulated by various tected only in vertebrate genomes, whereas most ubiquitin-like means and dysregulation of this signaling is associated with a va- protein systems are highly conserved throughout all eukaryotes riety of immune disorders (5). There are three groups of negative from yeast to human. Thus, the ISGylation system may have spe- regulators for type I IFN and other such cytokine signaling: several cialized functions related to host defense against pathogens in by guest on September 24, 2021 protein tyrosine phosphatases (Src homology proteins 1 and 2, higher eukaryotes. To date, three enzymes, UBE1L (E1), UBC8 CD45, protein tyrosine phosphatase 1B, and T cell protein tyrosine (E2), and UBP43 (USP18, isopeptidase) have been identified for phosphatase), suppressor of cytokine signaling (SOCS) proteins, the ISGylation and deISGylation processes (11–14). Genetic and protein inhibitor of activated STAT family members (5). knockout studies demonstrated that UBP43 activity is not essential Recently, we have demonstrated that UBP43, a deconjugating for the precursor processing of ISG15 in vivo because UBP43- protease of ISG15, is a new negative regulator of the type I IFN deficient cells can generate ISGylated proteins upon IFN treatment signaling pathway (6). ISG15 is an IFN-inducible ubiquitin-like (6). The most pronounced phenotype of UBP43 deficiency is hy- protein and its expression and conjugation to target proteins are persensitivity to type I IFN, with enhanced and prolonged activa- highly induced upon viral or bacterial infection (7, 8). The protein tion of Jak/Stat signaling (6). Thus, UBP43 is another member of the negative regulators of type I IFN and the Jak/Stat signaling pathway. Departments of *Molecular and Experimental Medicine and †Immunology, The Type I IFNs are produced in macrophages upon activation of Scripps Research Institute, La Jolla, CA 92037 TLR4 signaling by bacterial LPS, a pathogenic agent in endotoxin Received for publication March 21, 2005. Accepted for publication April 28, 2005. shock (15). Although TLRs have been shown to act as primary The costs of publication of this article were defrayed in part by the payment of page immune sensors for invading pathogens, over-activation of inflam- charges. This article must therefore be hereby marked advertisement in accordance matory signaling often causes a lethal shock to the host accompa- with 18 U.S.C. Section 1734 solely to indicate this fact. nied by multiple tissue damage and organ failure (16). TNF-␣ has 1 This work is supported by National Institutes of Health Grant CA079849 (to D.E.Z.) and GM060031 (to B.B.). The Stein Endowment Fund has partially supported the been known to be a major contributor to LPS-induced septic shock Molecular and Experimental Medicine Departmental Molecular Biology Service Lab- (17–19). In addition to TNF-␣, a recent report demonstrated that oratory for DNA Sequencing and Oligonucleotide Synthesis. This is manuscript no. type I IFNs, especially IFN-␤, are central effecters in LPS-induced 17087-MEM from The Scripps Research Institute. lethality (20). Several microarray studies showed that ISG15 is a 2 Current address: Department of Biological Science, Sookmyung Women’s Univer- sity, 53-12 Chungpa-dong 2 Ka, Yongsan-gu, Seoul 140-742, Korea. highly up-regulated gene in human macrophages during various 3 Address correspondence and reprint requests to Dr. Dong-Er Zhang, MEM-L51, bacterial infections (21, 22) and both ISG15 and UBP43 were iden- The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. tified as LPS-induced genes in mouse macrophages (23). We ques- E-mail address: [email protected] tioned whether ISG15 and/or UBP43 are involved in antibacterial 4 Abbreviations used in this paper: ISG, IFN-stimulated gene; BMM, bone marrow- responses mediated by TLR4 signaling and addressed this question derived macrophage; ISGylation, ISG15 protein conjugation; IRF, IFN regulatory factor; SOCS, suppressor of cytokine signaling; m, murine; IP-10, IFN-␥-inducible by using the UBP43 knockout mouse model, which is lacking an protein-10, Trif, TIR domain-containing adapter inducing IFN-␤. ISG15-specific deconjugating enzyme. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 848 ENHANCED ANTIBACTERIAL EFFICIENCY IN ubp43Ϫ/Ϫ MICE We report that LPS-induced UBP43 expression and protein IS- with the indicated magnification. The number of particles in the cells was Gylation is mainly a TIR domain-containing adapter inducing also counted from a total of 200 cells to get the average number of particles IFN-␤ (Trif) and type I IFN-dependent event in macrophages. We from each genotype of macrophages. also show that UBP43-deficient mice have a higher sensitivity to Northern blotting endotoxin-induced septic shock than wild-type mice. However, ␣ Total RNA from BMM was isolated using RNA Bee reagent according to TNF- production in UBP43-deficient macrophages was compa- the manufacturer’s instructions (Tel-Test). Five micrograms of total RNA rable to that of wild-type macrophages upon LPS treatment. In- from each time point was separated in an agarose/formaldehyde gel (0.22 stead, ubp43Ϫ/Ϫ macrophages exhibited enhanced and prolonged M), blotted on Hybond Nϩ membrane (Amersham Biosciences), and 32 activation of Jak/Stat signaling resulting in elevated expression of probed with P-labeled cDNAs. As an equal loading control, 28 S rRNA was detected using 32P-labeled probe (5Ј-AACGATGAGAGTAGTGG-3Ј) ISGs, as well as IFN-inducible cytokine and chemokine genes, by hybridizing at 43°C and washing with 6ϫ SSC containing 0.1% SDS which indicates a negative regulatory role of UBP43 in type I IFN at 43°C. signaling. ubp43Ϫ/Ϫ macrophages also showed enhanced phagocytic activity to IgG opsonized yeast particles. With these characteristics, Quantitative real-time PCR Ϫ Ϫ ubp43 / mice were more capable of restricting
Load more

Recommended publications
  • A Co-Opted ISG15-USP18 Binding Mechanism Normally Reserved for Deisgylation Controls Type I IFN Signalling
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.01.446527; this version posted June 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 A co-opted ISG15-USP18 binding mechanism normally reserved for deISGylation controls 2 type I IFN signalling 3 4 5 6 Andri Vasou1, Katie Nightingale2, Vladimíra Cetkovská 1, Connor G.G. Bamford3‡, Jelena 7 Andrejeva1, Richard E. Randall1, John McLauchlan3, Michael P. Weekes2, David J Hughes1* 8 9 10 11 1Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St 12 Andrews, United Kingdom. 2Cambridge Institute for Medical Research, Hills Road, Cambridge, 13 United Kingdom 3MRC-University of Glasgow Centre for Virus Research, Glasgow, United 14 Kingdom. 15 16 17 ‡ Present addresses: Wellcome-Wolfson Institute for Experimental Medicine, Queen’s 18 University, Belfast UK. 19 20 21 22 * Corresponding author: [email protected]; Tel: +44 1334 467197 23 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.01.446527; this version posted June 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 24 Abstract 25 Type I interferon (IFN) signalling induces the expression of several hundred IFN-stimulated 26 genes that provide an unfavourable environment for viral replication.
    [Show full text]
  • Genesis of Non-Coding RNA Genes in Human Chromosome 22—A Sequence Connection with Protein Genes Separated by Evolutionary Time
    non-coding RNA Perspective Genesis of Non-Coding RNA Genes in Human Chromosome 22—A Sequence Connection with Protein Genes Separated by Evolutionary Time Nicholas Delihas Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, NY 11794-5222, USA; [email protected] Received: 16 July 2020; Accepted: 1 September 2020; Published: 3 September 2020 Abstract: A small phylogenetically conserved sequence of 11,231 bp, termed FAM247, is repeated in human chromosome 22 by segmental duplications. This sequence forms part of diverse genes that span evolutionary time, the protein genes being the earliest as they are present in zebrafish and/or mice genomes, and the long noncoding RNA genes and pseudogenes the most recent as they appear to be present only in the human genome. We propose that the conserved sequence provides a nucleation site for new gene development at evolutionarily conserved chromosomal loci where the FAM247 sequences reside. The FAM247 sequence also carries information in its open reading frames that provides protein exon amino acid sequences; one exon plays an integral role in immune system regulation, specifically, the function of ubiquitin-specific protease (USP18) in the regulation of interferon. An analysis of this multifaceted sequence and the genesis of genes that contain it is presented. Keywords: de novo gene birth; gene evolution; protogene; long noncoding RNA genes; pseudogenes; USP18; GGT5; Alu sequences 1. Introduction The genesis of genes has been a major topic of interest for several decades [1,2]. One mechanism of gene formation is by duplication of existing genes [1,3].
    [Show full text]
  • USP18 Is a Key Regulator of the Interferon-Driven Gene Network Modulating Pancreatic Beta Cell Inflammation and Apoptosis
    Citation: Cell Death and Disease (2012) 3, e419; doi:10.1038/cddis.2012.158 & 2012 Macmillan Publishers Limited All rights reserved 2041-4889/12 www.nature.com/cddis USP18 is a key regulator of the interferon-driven gene network modulating pancreatic beta cell inflammation and apoptosis I Santin*,1, F Moore1, FA Grieco1, P Marchetti2, C Brancolini3 and DL Eizirik1 Type 1 diabetes (T1D) is an autoimmune disease targeting pancreatic beta cells. Genome-wide association studies and gene expression analysis identified interferon (IFN)-driven gene networks as crucial pathways in the pathogenesis of T1D. IFNs are linked to the response to viral infections and might contribute to the initiation of the autoimmune process in T1D. We presently analyzed the role of ubiquitin-specific peptidase 18 (USP18), an interferon-stimulated gene 15-specific protease, on IFN-induced pancreatic beta cell inflammation and apoptosis. Our findings indicate that USP18 inhibition induces inflammation by increasing the STAT signaling and exacerbates IFN-induced beta cell apoptosis by the mitochondrial pathway of cell death. USP18 regulates activation of three BH3-only proteins, namely, DP5, Bim and PUMA in pancreatic beta cells, suggesting a direct link between regulators of the type I IFN signaling pathway and members of the BCL-2 family. USP18 depletion increases the expression of the T1D candidate gene MDA5, leading to an upregulation of double-stranded RNA-induced chemokine production. These data suggest a cross talk between the type I IFN signaling pathway and a candidate gene for T1D to increase pro-inflammatory responses in beta cells. The present study shows that USP18 is a key regulator of IFN signaling in beta cells and underlines the importance of this pathway in beta cell inflammation and death.
    [Show full text]
  • STAT2 Is an Essential Adaptor in USP18-Mediated Suppression of Type I Interferon Signaling
    ARTICLES STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling Kei-ichiro Arimoto1,8, Sara Löchte2,8, Samuel A Stoner1, Christoph Burkart1, Yue Zhang3, Sayuri Miyauchi1, Stephan Wilmes2, Jun-Bao Fan1, Jürgen J Heinisch2, Zhi Li4, Ming Yan1, Sandra Pellegrini4, Frédéric Colland5,7, Jacob Piehler2 & Dong-Er Zhang1,3,6 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. We found that STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site. This mechanistic coupling of effector and negative-feedback functions of STAT2 may provide novel strategies for treatment of IFN-signaling-related human diseases. Type I interferon (IFN) signaling has emerged as a highly complex thereby resulting in formation of the DNA-binding STAT1–STAT2– regulatory network coordinating the host’s defense against pathogens IRF9 ternary complex IFN-stimulated gene factor 3 (ISGF3). ISGF3 and cancer via expression of over 300 IFN-stimulated genes (ISGs)1,2. promotes expression of genes with an IFN-stimulated response ele- Proteins encoded by ISGs include cytokines and chemokines that mod- ment in their promoters12,13.
    [Show full text]
  • Type I IFN Is Siloed in Endosomes BRIEF REPORT Jennie B
    Type I IFN is siloed in endosomes BRIEF REPORT Jennie B. Altmana, Justin Tafta, Tim Wedekingb, Conor N. Grubera, Michael Holtmannspötterb,c, Jacob Piehlerb,d, and Dusan Bogunovica,e,f,g,1 aDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; bDivision of Biophysics, Department of Biology, Osnabrück University, 49076 Osnabrück, Germany; cIntegrated Bioimaging Facility, Osnabrück University, 49076 Osnabrück, Germany; dCenter for Cellular Nanoanalytics, Osnabrück University, 49076 Osnabrück, Germany; eDepartment of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; fPrecision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and gMindich Child Heath and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Edited by Tak W. Mak, University of Toronto, Toronto, ON, Canada, and approved June 16, 2020 (received for review December 6, 2019) Type I IFN (IFN-I) is thought to be rapidly internalized and degraded ISGs in ISG15- and USP18-deficient cells, but not control cells following binding to its receptor and initiation of signaling. How- (Fig. 1B). Thus, transcription occurs long after the elimination of ever, many studies report the persistent effects mediated by IFN-I IFN-I in ISG15- and USP18-deficient cells. for days or even weeks, both ex vivo and in vivo. These long- We investigated molecules acting farther upstream and de- lasting effects are attributed to downstream signaling molecules tected pSTAT1 and pSTAT2 (mediators of IFN-I proximal sig- or induced effectors having a long half-life, particularly in specific naling) (9) in ISG15- and USP18-deficient cells, but not control cell types.
    [Show full text]
  • USP18 Is Differentially Expressed in SARS and MERS Coronavirus
    1 USP18 is differentially expressed in SARS and MERS coronavirus infection models. 2 Shahan Mamoor1 1Thomas Jefferson School of Law 3 East Islip, NY 11730 4 [email protected] 5 COVID19 is caused by infection with the seventh virus of the coronavirus family capable of infecting humans, now known as Severe Acute Respiratory Syndrome 2, or SARS-CoV-2 (1-3). 6 We mined published and public microarray data from coronavirus infection models to identify genes whose expression changed most significantly following infection with coronaviruses 7 (4-9). In two in vivo mouse models of SARS coronavirus infection, the ubiquitin-specific 8 protease USP18 was among the genes whose expression changed most significantly in the lungs of mice infected with SARS-CoV-1. In the blood of ferrets after intranasal infection with 9 SARS-CoV-1, and in human cells in vitro after infection with the Middle Eastern Respiratory Syndrome (MERS) coronavirus, Usp18 was also found to be differentially expressed when 10 compared to mock-infected tissues or uninfected cells. Differential expression of Usp18 following infection with coronaviruses can be observed in experimental models in vivo and in 11 vitro, and across species. 12 13 14 15 16 17 18 19 20 21 22 23 24 Keywords: COVID19, Usp18, SARS-CoV-2, systems biology of viral infection, coronaviruses. 25 26 27 28 1 OF 18 1 Coronavirus infection is a global health crisis (2) and over 80,000 people in the United 2 States have thus far lost their lives after infection with the novel coronavirus SARS-CoV-2 (10).
    [Show full text]
  • Negative Regulation of ACE2 by Interferons in Vivo and Its Genetic Control
    medRxiv preprint doi: https://doi.org/10.1101/2020.04.26.20080408; this version posted June 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Negative regulation of ACE2 by interferons in vivo and its genetic control M. Azim Ansari1,2,3,4*, Emanuele Marchi1,2,3*, Narayan Ramamurthy1,2,3*, Dominik Aschenbrenner1,3, Carl-Philipp Hackstein2, STOP-HCV consortium, ISARIC-4C Investigators, Shang-Kuan Lin4, Rory Bowden4, Eshita Sharma4, Vincent Pedergnana5, Suresh Venkateswaran6, Subra Kugathasan6, Angela Mo7, Greg Gibson7, Graham Cooke8, John McLauchlan9, Eleanor Barnes1,2,3, John Kenneth Baillie10,11, Sarah Teichmann12, Alex Mentzer4, 4 4 1,3,13 1,2,3 John Todd , Julian Knight , Holm Uhlig , Paul Klenerman * 1. Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK 2. Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK 3. NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford, OX3 9DU 4. Wellcome Centre for Human Genetics, Roosevelt Dr, Headington, Oxford OX3 7BN 5. French National Centre for Scientific Research (CNRS), Laboratory MIVEGEC (CNRS, IRD, UM), Montpellier, France 6. Department of Pediatrics, Emory University School of Medicine and Children’s health care of Atlanta, Atlanta, USA 7. Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, USA 8. Department of Infectious Disease, Faculty of Medicine, Imperial College London, London W2 1PG, UK 9.
    [Show full text]
  • How New RNA Genes Are Born
    Nicholas Delihas human FAM247 long intergenic non-coding RNA gene family Biology ︱ A model of gene formation involving these so-called pseudogenes has been presented by Dr Delihas whereby FAM247 forms human pseudogenes such as the FAM247 fragment serves as a POM121L9P nucleation element or a foundation site. Other sequence blocks from other parts of the genome are added How new RNA FAM247 spans evolutionary time to the FAM247 sequence to form the over 350 million years mature gene (see figure 2). These FAM247 fragments are in genomic regions that display evolutionarily conserved sequence signatures. The genes are born GGT5 –gamma-glutamyltransferase 5 protein gene found FAM247 sequence appears to carry in house mouse contains the 5’ half sequence of FAM247 the information for the attachment The study of gene birth and ene duplication, the formation Evolutionary scientists routinely survey of these extraneous sequences and evolution focuses on the of new genes from an exact the genetic architecture of human and it represents a focal point for the identification of ancestral Gcopy of existing ones, has long primate populations, along those of USP18 protein carboxy end sequence from FAM247: de novo genesis of this and other genetic sequences, highly been considered the major process other species, to find out the specific QETAYLLVYMKMEC372. A similar sequence is in zebrafish pseudogenes. These pseudogenes conserved during evolution, behind gene formation. However, it has roles that different genes play in the display RNA transcript expression, that can serve as a foundation been shown that genes may be born way different populations adapt to and several in a very broad and robust for gene development.
    [Show full text]
  • Emerging Roles of USP18: from Biology to Pathophysiology
    Review Emerging Roles of USP18: From Biology to Pathophysiology Ji An Kang 1,2 and Young Joo Jeon 1,2,* 1 Department of Biochemistry, Chungnam National University College of Medicine, Daejeon 35015, Korea; [email protected] 2 Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Korea * Correspondence: [email protected]; Tel: +82 42 280 6766, Fax: +82 42 280 6769 Received: 27 August 2020; Accepted: 14 September 2020; Published: 17 September 2020 Abstract: Eukaryotic proteomes are enormously sophisticated through versatile post-translational modifications (PTMs) of proteins. A large variety of code generated via PTMs of proteins by ubiquitin (ubiquitination) and ubiquitin-like proteins (Ubls), such as interferon (IFN)-stimulated gene 15 (ISG15), small ubiquitin-related modifier (SUMO) and neural precursor cell expressed, developmentally downregulated 8 (NEDD8), not only provides distinct signals but also orchestrates a plethora of biological processes, thereby underscoring the necessity for sophisticated and fine- tuned mechanisms of code regulation. Deubiquitinases (DUBs) play a pivotal role in the disassembly of the complex code and removal of the signal. Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, is a major DUB that reverses the PTM of target proteins by ISG15 (ISGylation). Intriguingly, USP18 is a multifaceted protein that not only removes ISG15 or ubiquitin from conjugated proteins in a deconjugating activity-dependent manner but also acts as a negative modulator of type I IFN signaling, irrespective of its catalytic activity. The function of USP18 has become gradually clear, but not yet been completely addressed. In this review, we summarize recent advances in our understanding of the multifaceted roles of USP18.
    [Show full text]
  • Isgylation and Inhibits TGF-Β1- Induced Fibronectin Expression
    Original research J Investig Med: first published as 10.1136/jim-2019-001145 on 23 December 2019. Downloaded from FOXO3a is stabilized by USP18- mediated de- ISGylation and inhibits TGF-β1- induced fibronectin expression Ban Wang,1 Yanhui Li,2,3 Heather Wang,3 Jing Zhao,3 Yutong Zhao ,3 Zhonghui Liu,1 Haichun Ma2 1Department of Immunology, ABSTRact College of Basic Medical FOXO3a belongs to a family of transcription factors Significance of this study Sciences, Jilin University, Changchun, China characterized by a conserved forkhead box DNA- 2 What is already known about this subject? Department of Anesthesia, binding domain. It has been known to regulate Jilin University First Hospital, various cellular processes including cell proliferation, ► FOXO3a regulates various cellular Changchun, China and biological functions including cell 3 apoptosis and differentiation. Post- translational Department of Physiology modifications of FOXO3a and their roles in the proliferation and death. and Cell Biology, Ohio State ► FOXO3a can be post- translational modified University, Columbus, Ohio, regulation of FOXO3a activity have been well- USA documented. FOXO3a can be phosphorylated, by phosphorylation, ubiquitination and acetylated and ubiquitinated, however, the acetylation. Correspondence to ISGylation of FOXO3a has not been reported. ► Post- translational modification regulates Dr Zhonghui Liu; Protein overexpression, ISGylation and half-life FOXO3a’s stability and activity. liuzh@ jlu. edu. cn were measured to determine the post- translational Dr Haichun Ma; What are the new findings? modification of FOXO3a. Human fibroblast cells were mahc@ jlu. edu. cn ► FOXO3a can be ISGylated. treated with transforming growth factor (TGF)- 1 to β ► ISGylation of FOXO3a determines FOXO3a Accepted 26 November determine the role of FOXO3a ISGylation in TGF-β1 half- life.
    [Show full text]
  • 1 TITLE 1 2 ISG15/USP18/STAT2 Is a Molecular Hub Regulating Autocrine
    bioRxiv preprint doi: https://doi.org/10.1101/784678; this version posted December 9, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 TITLE 2 3 ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I- 4 mediated control of Dengue and Zika virus replication 5 6 Constanza Eleonora Espada1, Edroaldo Lummertz da Rocha1, Adara Aurea 7 dos Santos1, Zamira Guerra Soares1, Greicy Malaquias1, Daniel Oliveira 8 Patrício1, Edgar Gonzalez Kozlova1, Paula Fernandes dos Santos1, Juliano 9 Bordignon2, Thomas J. Sanford3, Teodoro Fajardo3, Trevor R. Sweeney3, 10 André Báfica1, Daniel Santos Mansur1* 11 12 1Laboratório de Imunobiologia, Departamento de Microbiologia, Imunologia e 13 Parasitologia, Centro de Ciências Biológicas, Universidade Federal de Santa 14 Catarina, Santa Catarina CEP 88040-900, Brazil. 15 16 2Laboratório de Virologia Molecular, Instituto Carlos Chagas, ICC/Fiocruz-PR, 17 Curitiba, Paraná, CEP 81350-010, Brazil. 18 19 3Division of Virology, Department of Pathology, University of Cambridge, 20 Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK. 21 22 *Correspondence: [email protected] 23 24 SUMMARY 25 26 The establishment of a virus infection is the result of the pathogen’s ability to 27 replicate in a hostile environment generated by the host’s immune system. 28 Here, we found that ISG15 restricts Dengue and Zika viruses’ replication 29 through the stabilization of its binding partner USP18. ISG15 expression was 30 necessary to control DV replication driven by both autocrine and paracrine 31 type one interferon (IFN-I) signaling.
    [Show full text]
  • USP18) Expression This Information Is Current As of October 2, 2021
    The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression This information is current as of October 2, 2021. Jung-Hwan Kim, Jiann-Kae Luo and Dong-Er Zhang J Immunol 2008; 181:6467-6472; ; doi: 10.4049/jimmunol.181.9.6467 http://www.jimmunol.org/content/181/9/6467 Downloaded from References This article cites 45 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/181/9/6467.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression1 Jung-Hwan Kim,2* Jiann-Kae Luo,3* and Dong-Er Zhang4*† Hepatitis B virus (HBV) causes both acute and chronic infection of the human liver and is associated with the development of liver cirrhosis and hepatocellular carcinoma.
    [Show full text]