DOCSLIB.ORG

Viral Hijacking of Host Caspases: an Emerging Category of Pathogen&Ndash

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Viral Hijacking of Host Caspases: an Emerging Category of Pathogen&Ndash Cell Death and Differentiation (2017) 24, 1401–1410 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17 www.nature.com/cdd Review Viral hijacking of host caspases: an emerging category of pathogen–host interactions Patrick F Connolly1 and Howard O Fearnhead*,1 Viruses co-evolve with their hosts, and many viruses have developed mechanisms to suppress or modify the host cell apoptotic response for their own benefit. Recently, evidence has emerged for the opposite strategy. Some viruses have developed the ability to co-opt apoptotic caspase activity to facilitate their own proliferation. In these strategies, viral proteins are cleaved by host caspases to create cleavage products with novel activities which facilitate viral replication. This represents a novel and interesting class of viral–host interactions, and also represents a new group of non-apoptotic roles for caspases. Here we review the evidence for such strategies, and discuss their origins and their implications for our understanding of the relationship between viral pathogenesis and programmed cell death. Cell Death and Differentiation (2017) 24, 1401–1410; doi:10.1038/cdd.2017.59; published online 19 May 2017 Bullet Points It is also important to note that even during apoptosis, caspases engage not only in destructive cleavage, but also Facts engage in productive cleavage: cleavage which produces de novo activities of the substrate protein. This is achieved Executioner caspases have many non-apoptotic roles. through several mechanisms (Figure 1), such as removal of Many viruses modulate the host cell apoptotic response. autoinhibitory domains to produce constitutively active Some viruses utilize caspases to perform proteolytic enzymes, cleavage of cytoplasmic localization sequences to processing of viral components. facilitate nuclear membrane transition, or degradation of Caspase-3 and -7 predominate, although caspase-6 upstream inhibitory factors in metabolic pathways to activate – cleavage is also used. downstream factors.3 6 Such productive cleavage allows Open questions apoptotic cells to engage signaling pathways until late in the cell death process. How widespread is this phenomenon? No systematic Host cell apoptosis is a common response to viral infection et al 7 experiments have yet been published. (reviewed in Galluzzi . ). Apoptosis is typically considered Can these examples be classified into functional a defense mechanism which kills the infected cell in order to categories? protect the organism as a whole. As a result of this, there is a Did this ‘hijacking’ emerge once or several times during selection pressure in favor of viruses which have evolved evolution? mechanisms to block apoptosis. For example, several viruses Are other modalities of cell death manipulated in this way? encode Bcl-2 homologs or homologs of cFLIP which function to inhibit activation of apoptotic caspases and block death of 8–16 Caspases can be classed into three broad categories (Table 1): the host cell. those which function as the proteolytic executioners of Interestingly, the inverse strategy can also be observed. apoptosis (‘killer’ caspases; including -3 and -7), those which Some viruses actually exploit host cell caspase activity serve to activate the executioner caspases (initiator caspases; to facilitate their own replication. These viruses encode including -8 and -10), and those which have roles in non- gene products with canonical caspase cleavage motifs, apoptotic processes, including inflammatory caspases such and cleavage at these sites produces products with as -1, -5 and -11 (reviewed in Earnshaw et al.1 and Martinon additional functions. This caspase cleavage is used, for and Tschopp2). example, to facilitate nuclear translocation of viral compo- In recent years it has become clear that ‘killer’ caspases nents, to activate viral-encoded host transcriptional modifiers, have roles in diverse non-apoptotic processes, such as cell or to perform final maturation of virion particles (summarized in differentiation, migration and metastasis, and in signaling Table 2). (reviewed in other articles in this issue). In these non-apoptotic The involvement of host caspases in both viral and bacterial processes, the extent of caspase activation or its subcellular pathogenesis has previously been reviewed.17,18 However the localization is restricted in order to prevent cell death. present review focuses solely on examples of host caspase 1Pharmacology and Therapeutics, School of Medicine, National University of Ireland Galway, Galway, Ireland *Corresponding author: H Fearnhead, Pharmacology and Therapeutics National University of Ireland, Galway, Biomedical Sciences Building Newcastle Road Room BMS-G029 NUI Galway, Dangan, Galway H91 CF50, Ireland; Tel: +353 91 495240. E-mail: howard.fearnhead@nuigalway.ie Received 17.1.17; revised 14.3.17; accepted 27.3.17; Edited by E Arama; published online 19.5.17 1402 Cell Death and Differentiation CDK1) through inactivation of upstreaminhibitor inhibitory partners factors (ICAD/CAD), in through biochemical removalsignaling of pathways factors autoinhibitory or (Wee1/ domains enzymes (PAK2), are or activated. Thisexecutioner can be caspases through degradation can of bound disassembling also the engage cytoskeleton through induring cleavage apoptosis. of productive Executioner actin caspases cleavage can filaments engage (right), (left). in destructive However, cleavage, in such as which As such, a review of thecaspase current state interactions of this being research published ishas timely. at an continued increasedapoptosis to pace. as develop, progeny withcleavage dissemination of viral mechanism. proteins new rather This than, examples for example, field induction of of virus Figure 1 functions. differentiation (cornification). Capsasesthe conventional 16 groups. Caspase-14apoptosis appears initiators to and function apoptosis onlyCaspases executioners. are in Some typically keratinocyte caspases grouped into lie three outside major of types: inflammatory caspases, Unknown functionsKeratinocyte differentiationApoptotic executioner Caspase-14 Caspase-16Apoptotic initiator Caspase-3 119 120 Inflammatory responseFunctional group 116 Caspase-2Table 1 Caspase-1 111 Name 105 Ref Conventional roles of caspases in cell death and inflammation 119 Examples of destructive and productive cleavage events by caspases – 18 have not yet been ascribed Caspase-18Caspase-17Caspase-7Caspase-6 120 120 Caspase-15Caspase-10Caspase-9 118 Caspase-8 117 Caspase-13 115 Caspase-12 114 Caspase-11 113 Caspase-5 112 Caspase-4 110 109 108 107 106 Viral hijacking of host caspases PF Connolly and HO Fearnhead – Table 2 Summary of examples of productive caspase cleavage presented in this review Family Species Protein Protein role Caspase Cleavage site Consequence of cleavage Primary (full length) reference Parvoviridae Amdovirus NS1 Gene transcription and 3 INTD/227, DQTD/285 Cleaved NS1 acts as a chaperone to deliver full- 26 translation (590) length NS1 to nucleus Orthomyxoviridae Influenza A NP Structural protein 3 METD/16 (498) Removal of nuclear localization sequence, 30 translocation of ribonucleoprotein complexes to cytoplasm Flaviviridae Hepacivirus C NS5A Modulates host gene tran- 3 TELD/154, SAVD/389 Exposure of nuclear localization sequence, 46 scription and inflammatory (447) removal of cytoplasmic localization sequence. response Translocation of NS5A to nucleus Flaviviridae Classical swine fever NS5A Viral genome translation 6 DTTD/275 (497) Unknown. Viral replication severely impaired 84 virus under caspase-6 inhibition Papillomaviridae Human E1 DNA helicase 3/7 DMVD/49 (629) Facilitates viral genome amplification. May 58 papillomavirus expose a KRK nuclear localization signal. Adenoviridae Adenovirus-12 E1A-12S/ Modulates host gene 3 HLVD/24, FQLD/150, Disrupts binding to CBP and TBP and enhances 66 13S transcription STLD/204, SILD/222 binding to CTBP1 (266) Astroviridae Mamastrovirus VP90 Structural protein 3 TYVD/657 (782) VP90 processed into mature VP70. Contributes 75 to viral release Reoviridae Avian reovirus μNS Assembly of viral factories 3 DSPD/154 (635) Probably facilitates factory dissolution upon 80 completion of viral assembly For each viral protein, the responsible caspase, cleavage site, consequence of cleavage, and primary reference are summarized. Viral hijacking of host caspases PF Connolly and HO Fearnhead 1403 Cleavage to Induce Nuclear-Cytoplasmic Trafficking of Influenza A. Influenza viruses are members of the Ortho- Viral Components myxoviridae, a large family of ( − )ssRNA enveloped viruses which infect birds and mammals. There are currently three Amdovirus. The Aleutian mink disease parvovirus (AMDV, recognized subtypes of influenza, termed A, B and C.27 All Amdovirus) is a small, nonenveloped, (− )ssDNA virus.19 It Influenza subtypes share similar overall structure, consisting harbors a 4.7 kbp genome encoding two open reading of a lipid outer envelope, a capsid shell and a genomic frames, early ORF1 and late ORF2.20 ribonucleoprotein complex.28 ADV infects both newborn and adult minks, but with rather Caspase activity is required for replication of several different cytopathologies. In newborn minks, infection leads to pathogenic H7N7, H3N2 and H1N1 strains.29–31 Inhibition of rampant, permissive replication, causing apoptosis of the host caspase activity using z-DEVD.FMK causes significant cell. In adult minks, ADV maintains itself through a more replication deficiencies in
Load more

Recommended publications
  • Entry and Early Infection of Non-Segmented Negative Sense Rna Viruses
    University of Kentucky UKnowledge Theses and Dissertations--Molecular and Cellular Biochemistry Molecular and Cellular Biochemistry 2021 ENTRY AND EARLY INFECTION OF NON-SEGMENTED NEGATIVE SENSE RNA VIRUSES Jean Mawuena Branttie University of Kentucky, jean.m.branttie@gmail.com Digital Object Identifier: https://doi.org/10.13023/etd.2021.248 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Branttie, Jean Mawuena, "ENTRY AND EARLY INFECTION OF NON-SEGMENTED NEGATIVE SENSE RNA VIRUSES" (2021). Theses and Dissertations--Molecular and Cellular Biochemistry. 54. https://uknowledge.uky.edu/biochem_etds/54 This Doctoral Dissertation is brought to you for free and open access by the Molecular and Cellular Biochemistry at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Molecular and Cellular Biochemistry by an authorized administrator of UKnowledge. For more information, please contact UKnowledge@lsv.uky.edu. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • Viral Strategies to Arrest Host Mrna Nuclear Export
    Viruses 2013, 5, 1824-1849; doi:10.3390/v5071824 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Nuclear Imprisonment: Viral Strategies to Arrest Host mRNA Nuclear Export Sharon K. Kuss *, Miguel A. Mata, Liang Zhang and Beatriz M. A. Fontoura Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; E-Mails: Miguel.Mata@utsouthwestern.edu (M.A.M.); Liang6.Zhang@utsouthwestern.edu (L.Z.); Beatriz.Fontoura@utsouthwestern.edu (B.M.A.F) * Author to whom correspondence should be addressed; E-Mail: Sharon.Kuss@utsouthwestern.edu; Tel.: +1-214-633-2001; Fax: +1-214-648-5814. Received: 10 June 2013; in revised form: 27 June 2013 / Accepted: 11 July 2013 / Published: 18 July 2013 Abstract: Viruses possess many strategies to impair host cellular responses to infection. Nuclear export of host messenger RNAs (mRNA) that encode antiviral factors is critical for antiviral protein production and control of viral infections. Several viruses have evolved sophisticated strategies to inhibit nuclear export of host mRNAs, including targeting mRNA export factors and nucleoporins to compromise their roles in nucleo-cytoplasmic trafficking of cellular mRNA. Here, we present a review of research focused on suppression of host mRNA nuclear export by viruses, including influenza A virus and vesicular stomatitis virus, and the impact of this viral suppression on host antiviral responses. Keywords: virus; influenza virus; vesicular stomatitis virus; VSV; NS1; matrix protein; nuclear export; nucleo-cytoplasmic trafficking; mRNA export; NXF1; TAP; CRM1; Rae1 1. Introduction Nucleo-cytoplasmic trafficking of proteins and RNA is critical for proper cellular functions and survival.
    [Show full text]
  • Structure and Function of the Influenza a Virus Non-Structural Protein 1 Chang Woo Han1†, Mi Suk Jeong2†, and Se Bok Jang1*
    J. Microbiol. Biotechnol. (2019), 29(8), 1184–1192 https://doi.org/10.4014/jmb.1903.03053 Research Article Review jmb Structure and Function of the Influenza A Virus Non-Structural Protein 1 Chang Woo Han1†, Mi Suk Jeong2†, and Se Bok Jang1* 1Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea 2Korea Nanobiotechnology Center, Pusan National University, Busan 46241, Republic of Korea Received: March 25, 2019 Revised: May 27, 2019 The influenza A virus is a highly infectious respiratory pathogen that sickens many people Accepted: June 3, 2019 with respiratory disease annually. To prevent outbreaks of this viral infection, an First published online understanding of the characteristics of virus-host interaction and development of an anti-viral June 4, 2019 agent is urgently needed. The influenza A virus can infect mammalian species including *Corresponding author humans, pigs, horses and seals. Furthermore, this virus can switch hosts and form a novel Phone: +82-51-510-2523; lineage. This so-called zoonotic infection provides an opportunity for virus adaptation to the Fax: +82-51-581-2544; E-mail: sbjang@pusan.ac.kr new host and leads to pandemics. Most influenza A viruses express proteins that antagonize the antiviral defense of the host cell. The non-structural protein 1 (NS1) of the influenza A † These authors contributed virus is the most important viral regulatory factor controlling cellular processes to modulate equally to this work. host cell gene expression and double-stranded RNA (dsRNA)-mediated antiviral response. This review focuses on the influenza A virus NS1 protein and outlines current issues including the life cycle of the influenza A virus, structural characterization of the influenza A virus NS1, interaction between NS1 and host immune response factor, and design of inhibitors resistant pISSN 1017-7825, eISSN 1738-8872 to the influenza A virus.
    [Show full text]
  • Intergenotypic Replacement of Lyssavirus Matrix Proteins Demonstrates the Role of Lyssavirus M Proteins in Intracellular Virus A
    JOURNAL OF VIROLOGY, Feb. 2010, p. 1816–1827 Vol. 84, No. 4 0022-538X/10/$12.00 doi:10.1128/JVI.01665-09 Copyright © 2010, American Society for Microbiology. All Rights Reserved. Intergenotypic Replacement of Lyssavirus Matrix Proteins Demonstrates the Role of Lyssavirus M Proteins in Intracellular Virus Accumulationᰔ Stefan Finke,1* Harald Granzow,2 Jose Hurst,1† Reiko Pollin,1 and Thomas C. Mettenleiter1 Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institutes of Molecular Biology1 and Infectology,2 D-17493 Greifswald–Insel Riems, Germany Received 8 August 2009/Accepted 21 November 2009 Lyssavirus assembly depends on the matrix protein (M). We compared lyssavirus M proteins from different genotypes for their ability to support assembly and egress of genotype 1 rabies virus (RABV). Transcomple- Downloaded from mentation of M-deficient RABV with M from European bat lyssavirus (EBLV) types 1 and 2 reduced the release of infectious virus. Stable introduction of the heterogenotypic M proteins into RABV led to chimeric viruses with reduced virus release and intracellular accumulation of virus genomes. Although the chimeras indicated genotype-specific evolution of M, rapid selection of a compensatory mutant suggested conserved mechanisms of lyssavirus assembly and the requirement for only few adaptive mutations to fit the heterogenotypic M to a RABV backbone. Whereas the compensatory mutant replicated to similar infectious titers as RABV M- expressing virus, ultrastructural analysis revealed that both nonadapted EBLV M chimeras and the compen- jvi.asm.org satory mutant differed from RABV M expressing viruses in the lack of intracellular viruslike structures that are enveloped and accumulate in cisterna of the degranulated and dilated rough endoplasmic reticulum compartment.
    [Show full text]
  • Incorporation of Hepatitis C Virus E1 and E2 Glycoproteins: the Keystones on a Peculiar Virion
    Viruses 2014, 6, 1149-1187; doi:10.3390/v6031149 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Incorporation of Hepatitis C Virus E1 and E2 Glycoproteins: The Keystones on a Peculiar Virion Gabrielle Vieyres 1,*, Jean Dubuisson 2,3,4,5 and Thomas Pietschmann 1 1 Institute of Experimental Virology, Twincore, Center for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover and the Helmholtz Center for Infection Research, 30625 Hannover, Germany; E-Mail: thomas.pietschmann@twincore.de 2 Institut Pasteur de Lille, Center for Infection & Immunity of Lille (CIIL), F-59019 Lille, France; E-Mail: jean.dubuisson@ibl.fr 3 CNRS UMR8204, F-59021 Lille, France 4 Inserm U1019, F-59019 Lille, France 5 Université Lille Nord de France, F-59000 Lille, France * Author to whom correspondence should be addressed; E-Mail: gabrielle.vieyres@twincore.de; Tel.: +49-511-22-00-27-134; Fax: +49-511-22-00-27-139. Received: 18 December 2013; in revised form: 21 February 2014 / Accepted: 27 February 2014 / Published: 11 March 2014 Abstract: Hepatitis C virus (HCV) encodes two envelope glycoproteins, E1 and E2. Their structure and mode of fusion remain unknown, and so does the virion architecture. The organization of the HCV envelope shell in particular is subject to discussion as it incorporates or associates with host-derived lipoproteins, to an extent that the biophysical properties of the virion resemble more very-low-density lipoproteins than of any virus known so far. The recent development of novel cell culture systems for HCV has provided new insights on the assembly of this atypical viral particle.
    [Show full text]
  • Localization of Influenza Virus Proteins to Nuclear Dot 10 Structures in Influenza Virus-Infected Cells
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Available online at www.sciencedirect.com R Virology 310 (2003) 29–40 www.elsevier.com/locate/yviro Localization of influenza virus proteins to nuclear dot 10 structures in influenza virus-infected cells Yoshiko Sato,a Kenichi Yoshioka,a Chie Suzuki,a Satoshi Awashima,a Yasuhiro Hosaka,a Jonathan Yewdell,b and Kazumichi Kurodaa,c,* a Department of Virology and Immunology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan b Laboratory of Viral Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA c Department of Immunology and Microbiology, Nihon University School of Medicine, Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan Received 22 July 2002; returned to author for revision 19 August 2002; accepted 4 December 2002 Abstract We studied influenza virus M1 protein by generating HeLa and MDCK cell lines that express M1 genetically fused to green fluorescent protein (GFP). GFP-M1 was incorporated into virions produced by influenza virus infected MDCK cells expressing the fusion protein indicating that the fusion protein is at least partially functional. Following infection of either HeLa or MDCK cells with influenza A virus (but not influenza B virus), GFP-M1 redistributes from its cytosolic/nuclear location and accumulates in nuclear dots. Immunofluorescence revealed that the nuclear dots represent nuclear dot 10 (ND10) structures. The colocalization of authentic M1, as well as NS1 and NS2 protein, with ND10 was confirmed by immunofluorescence following in situ isolation of ND10.
    [Show full text]
  • The Role of MDM2–P53 Axis Dysfunction in the Hepatocellular
    Cao et al. Cell Death Discovery (2020) 6:53 https://doi.org/10.1038/s41420-020-0287-y Cell Death Discovery REVIEW ARTICLE Open Access TheroleofMDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation Hui Cao1, Xiaosong Chen2, Zhijun Wang3,LeiWang1,QiangXia2 and Wei Zhang1 Abstract Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2–p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2–p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes’ transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4+T cells by disrupting their MDM2–p53 axis.
    [Show full text]
  • Features of Nuclear Export Signals of NS2 Protein of Influenza D Virus
    viruses Article Features of Nuclear Export Signals of NS2 Protein of Influenza D Virus Lingcai Zhao, Huizhi Xia, Jingjin Huang, Yiqing Zheng, Chang Liu, Juan Su and Jihui Ping * MOE Joint International Research Laboratory of Animal Health and Food Safety, Engineering Laboratory of Animal Immunity of Jiangsu Province, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; 2018207020@njau.edu.cn (L.Z.); 2019807145@stu.njau.edu.cn (H.X.); huangjingjin1203@163.com (J.H.); 2019107060@njau.edu.cn (Y.Z.); changliu97@yahoo.com (C.L.); sujuan@njau.edu.cn (J.S.) * Correspondence: jihui.ping@njau.edu.cn Received: 10 September 2020; Accepted: 23 September 2020; Published: 29 September 2020 Abstract: Emerging influenza D viruses (IDVs), the newest member in the genus Orthomyxovirus family, which can infect and transmit in multiple mammalian species as its relatives the influenza A viruses (IAVs). Additional studies of biological characteristics of IDVs are needed; here, we studied the characteristics of IDV nonstructural protein 2 (NS2), which shares the lowest homology to known influenza proteins. First, we generated reassortant viruses via reverse genetics to analyze the segment compatibility and gene interchangeability between IAVs and IDVs. Next, we investigated the locations and exact sequences of nuclear export signals (NESs) of the IDV NS2 protein. Surprisingly, three separate NES regions were found to contribute to the nuclear export of an eGFP fusion protein. Alanine scanning mutagenesis identified critical amino acid residues within each NES, and co-immunoprecipitation experiments demonstrated that their nuclear export activities depend on the CRM1-mediated pathway, particularly for the third NES (136-146aa) of IDV NS2.
    [Show full text]
  • Viroporins: Structure, Function and Potential As Antiviral Targets
    This is a repository copy of Viroporins: Structure, function and potential as antiviral targets. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/88837/ Version: Accepted Version Article: Scott, C and Griffin, S orcid.org/0000-0002-7233-5243 (2015) Viroporins: Structure, function and potential as antiviral targets. Journal of General Virology, 96 (8). pp. 2000-2027. ISSN 0022-1317 https://doi.org/10.1099/vir.0.000201 © 2015 The Authors. Published by the Microbiology Society. This is an author produced version of a paper published in Journal of General Virology. Uploaded in accordance with the publisher's self-archiving policy. Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version - refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher’s website. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request. eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Journal of General Virology Viroporins: structure, function and potential as antiviral targets --Manuscript Draft-- Manuscript Number: VIR-D-15-00200R1 Full Title: Viroporins: structure, function and potential as antiviral targets Article Type: Review Section/Category: High Priority Review Corresponding Author: Stephen D.
    [Show full text]
  • Hepatitis C Virus NS2 Protein Suppresses RNA Interference in Cells
    Virologica Sinica (2020) 35:436–444 www.virosin.org https://doi.org/10.1007/s12250-019-00182-5 www.springer.com/12250 (0123456789().,-volV)(0123456789().,-volV) RESEARCH ARTICLE Hepatitis C Virus NS2 Protein Suppresses RNA Interference in Cells 1 1,2 2,3 2,4 2,4 2 2,4 Hui Zhou • Qi Qian • Ting Shu • Jiuyue Xu • Jing Kong • Jingfang Mu • Yang Qiu • Xi Zhou1,2,4 Received: 12 October 2019 / Accepted: 1 November 2019 / Published online: 27 November 2019 Ó Wuhan Institute of Virology, CAS 2019 Abstract RNAi interference (RNAi) is an evolutionarily conserved post-transcriptional gene silencing mechanism and has been well recognized as an important antiviral immunity in eukaryotes. Numerous viruses have been shown to encode viral sup- pressors of RNAi (VSRs) to antagonize antiviral RNAi. Hepatitis C virus (HCV) is a medically important human pathogen that causes acute and chronic hepatitis. In this study, we screened all the nonstructural proteins of HCV and found that HCV NS2 could suppress RNAi induced either by small hairpin RNAs (shRNAs) or small interfering RNAs (siRNAs) in mammalian cells. Moreover, we demonstrated that NS2 could suppress RNAi via its direct interaction with double- stranded RNAs (dsRNAs) and siRNAs, and further identified that the cysteine 184 of NS2 is required for the RNAi suppression activity through a serial of point mutation analyses. Together, our findings uncovered that HCV NS2 can act as a VSR in vitro, thereby providing novel insights into the life cycle and virus-host interactions of HCV. Keywords Hepatitis C virus (HCV) Á NS2 Á Antiviral RNAi Á Viral suppressor of RNAi (VSR) Introduction ion channel protein, and nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B (Yin et al.
    [Show full text]
  • Plugging the Holes in Hepatitis C Virus Antiviral Therapy
    COMMENTARY Plugging the holes in hepatitis C virus antiviral therapy Stephen D. C. Griffin1 Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Mount Preston Street, Leeds LS2 9JT, United Kingdom growing number of RNA vi- ruses are now known to de- pend on virus-encoded ion channels for efficient produc- Ation of infectious virions and, in some cases, for the subsequent infection of naı¨ve cells. So-called viroporins are small hydrophobic proteins, usually less than 100 aa in length, and typically con- tain 1 or 2 transmembrane domains (TMDs); oligomerization is therefore necessary for the formation of ion channel complexes. By far the best- characterized viroporin is the M2 proton channel of influenza A virus, which is the target for the antiviral drugs aman- tadine and rimantadine (1). M2 sets a precedent for viroporins as therapeutic targets that has driven research into the ion channels of other clinically impor- tant viruses. In the light of rapid RNA virus evolution generating drug resis- tance, new compounds targeting viro- porins could be a valuable addition to future combinatorial antiviral strategies. Difficulties associated with working with membrane proteins in high-throughput systems lend support to a rational ap- proach for drug development based on the availability of high-resolution molecular structures. In this issue of PNAS, Luik et al. (2), describe the first structure of a complete viroporin complex, the p7 ion channel of hepatitis C virus (HCV), at 16-Å res- olution by using single-particle electron microscopy. The hexameric p7 complex (42 kDa) is one of the smallest objects Fig.
    [Show full text]
  • Hepatitis B Virus X Protein Binding to Hepsin Promotes C3 Production by Inducing IL-6 Secretion from Hepatocytes
    www.impactjournals.com/oncotarget/ Oncotarget Vol. 7, No. 7 Hepatitis B virus X protein binding to hepsin promotes C3 production by inducing IL-6 secretion from hepatocytes Mingming Zhang1, Jianxin Gu1, Chunyi Zhang1 1 Department of Biochemistry and Molecular Biology, Gene Research Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China Correspondence to: Chunyi Zhang, e-mail: cyzhang@fudan.edu.cn Keywords: hepatitis B virus X protein, hepsin, complement C3, interleukin-6, hepatocellular carcinoma Received: August 06, 2015 Accepted: January 01, 2016 Published: January 08, 2016 ABSTRACT Hepatitis B virus (HBV) X protein (HBx) is an important effector for HBV- associated pathogenesis. In this study, we identified hepsin as an HBx-interacting protein and investigated the effects of hepsin on HBx-mediated complement component 3 (C3) secretion in hepatocytes. In vivo and in vitro binding between HBx and hepsin was confirmed by co-immunoprecipitation and Glutathione S-transferase pull-down assays. HBx synergized with hepsin to promote C3 production by potentiating interleukin-6 (IL-6) secretion. Knockdown of endogenous hepsin attenuated C3 and IL-6 secretion induced by HBx in hepatic cells. In addition, levels of hepsin protein correlated positively with C3 expression in human non-tumor liver tissues. Further exploration revealed that HBx and hepsin increased C3 promoter activity by up-regulating the expression and phosphorylation of the transcription factor CAAT/enhancer binding protein beta (C/EBP-β), which binds to the IL-6/ IL-1 response element in the C3 promoter. HBx and hepsin synergistically enhanced IL-6 mRNA levels and promoter activity by increasing the nuclear translocation of nuclear factor kappaB (NF-κB).
    [Show full text]