Topological Analysis of the Gp41 MPER on Lipid Bilayers Relevant to the Metastable HIV-1 Envelope Prefusion State
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The 3-Dimensional Structure of a Hepatitis C Virus P7 Ion Channel by Electron Microscopy
The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy Philipp Luika, Chee Chewb, Jussi Aittoniemib, Jason Changc, Paul Wentworth, Jrc, Raymond A. Dweka, Philip C. Bigginb, Catherine Ve´ nien-Bryand, and Nicole Zitzmanna,1 Department of Biochemistry and aOxford Glycobiology Institute, bStructural Bioinformatics and Computational Biochemistry, cThe Scripps/Oxford Laboratory, and dLaboratory of Molecular Biophysics, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom Communicated by Charles M. Rice, The Rockefeller University, New York, NY, May 29, 2009 (received for review December 23, 2008) Infection with the hepatitis C virus (HCV) has a huge impact on have suggested that monomers assemble into either hexamers global health putting more than 170 million people at risk of (10) or heptamers (9) in lipid bilayers. developing severe liver disease. The HCV encoded p7 ion channel We report here the 3-dimensional (3D) structure of an HCV is essential for the production of infectious viruses. Despite a p7 ion channel. Chemically synthesized p7 monomers of native growing body of functional data, little is known about the 3-di- length and charge were solubilized in detergent. The resulting mensional (3D) structure of the channel. Here, we present the 3D oligomeric channels were negatively stained, imaged, and ana- structure of a full-length viroporin, the detergent-solubilized hex- lyzed using single particle reconstruction. The 3D structure was americ 42 kDa form of the HCV p7 ion channel, as determined by determined by the random conical tilt approach at a resolution single-particle electron microscopy using the random conical tilting of Ϸ16 Å. -
Viewed in Mclaughlin-Drubin and Munger, 2008)
MIAMI UNIVERSITY The Graduate School Certificate for Approving the Dissertation We hereby approve the Dissertation of Anand Prakash Candidate for the Degree: Doctor of Philosophy Dr. Eileen Bridge, Mentor Dr. Gary R. Janssen, Reader Dr. Joseph M. Carlin, Reader Dr. Xiao-Wen Cheng Dr. David G. Pennock Graduate School Representative ABSTRACT INVESTIGATING THE TRIGGERS FOR ACTIVATING THE CELLULAR DNA DAMAGE RESPONSE DURING ADENOVIRUS INFECTION by Anand Prakash Cellular genomic integrity is constantly attacked by a variety of exogenous and endogenous agents. In response to damaged DNA, the cell activates a DNA damage response (DDR) pathway to maintain genomic integrity. Cells can also activate DDRs in response to infection with several types of viruses. The cellular DDR pathway involves sensing DNA damage by the Mre11, Rad50, Nbs1 (MRN) sensor complex, which activates downstream ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) kinases. These kinases phosphorylate downstream effector proteins implicated in cell cycle arrest, DNA repair, and, if the damage is irreparable, apoptosis. The induction of DDRs includes focal accumulation and phosphorylation of several DDR proteins. Adenovirus (Ad) mutants that lack early region 4 (E4) activate a cellular DDR. E4 proteins normally inactivate the MRN sensor complex and prevent downstream DDR signaling involved in DNA repair and cell cycle checkpoint arrest in wild- type Ad5 infections. The characteristics of Ad infection that activate the cellular DDR are not well understood. We have investigated the ability of replication defective and replication competent Ad mutants to activate cellular DDRs and G2/M cell cycle arrest. Ad infection induced early focal accumulation of DDR proteins such as Mre11, Mdc1, phosphorylated ATM (pATM), phosphorylated Chk2 (pChk2), and 53BPI, independent of the replication status of the mutants studied. -
Entry of Hepatitis B and C Viruses
VIRAL HEPATITIS FORUM Getting Close Viralto Eradication Hepatitis Forum I. Basic Getting Research Close to Eradication I. Basic Research Entry of Hepatitis B and C Viruses Seungtaek Kim Severance Biomedical Science Institute, Institute of Gastroenterology, Department of Internal Medicine, Yonsei University Col- lege of Medicine, Seoul, Korea B형과 C형 간염 바이러스에 대한 최근의 분자, 세포생물학적인 발전은 간세포를 특이적으로 감염시키는 이들 바이러스에 대한 세포 수용체의 발굴과 더불어 그들의 작용 기전에 대해 더 자세한 정보들을 제공해주고 있다. 특히 C형 간염 바이러스의 경우, 간세포의 서로 다른 곳에 위치한 세포 수용체들이 바이러스의 세포 진입시에 바이러스 표면의 당단백질과 어떤 방식으로 서로 상호 작용하며 세포 내 신호 전달 과정을 거쳐 세포 안으로 들어오게 되는지 그 기전들이 서서히 드러나고 있다. 한편, B형 간염 바이러스의 경우, 오랫동안 밝혀내지 못했던 이 바이러스의 세포 수용체인 NTCP를 최근 발굴하게 됨으로써 세포 진입에 관한 연구에 획기적인 계기를 마련하게 되었으며 동시에 이를 저해할 수 있는 새로운 항바이러스제의 개발도 활기를 띠게 되었다. 임상적으로 매우 중요한 이 두 바이러스의 세포 진입에 관한 연구는 앞으로도 매우 활발하게 이루어질 것으로 기대된다. Keywords: B형 간염 바이러스, C형 간염 바이러스, 세포 진입, 신호 전달, NTCP There are five hepatitis viruses although their classes, genomes, and modes of transmission are different from each other. Of these, hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most dangerous, life-threatening pathogens, which are also responsible for 80-90% of hepatocellular carcinoma. HBV belongs to hepadnaviridae (family) and it has double-strand DNA as its genome, however, its replication occurs via reverse transcription like retrovirus replication. In contrast, HCV belongs to flaviviridae (family) and has positive-sense, single-strand RNA as its genome. -
Herpes Simplex Virus Type 1 Oril Is Not Required for Virus Infection In
JOURNAL OF VIROLOGY, Nov. 1987, p. 3528-3535 Vol. 61, No. 11 0022-538X/87/113528-08$02.00/0 Copyright C 1987, American Society for Microbiology Herpes Simplex Virus Type 1 oriL Is Not Required for Virus Replication or for the Establishment and Reactivation of Latent Infection in Mice MARYELLEN POLVINO-BODNAR, PAULO K. ORBERG, AND PRISCILLA A. SCHAFFER* Laboratory of Tumor Virus Genetics, Dana-Farber Cancer Institute, and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115 Received 11 May 1987/Accepted 31 July 1987 During the course of experiments designed to isolate deletion mutants of herpes simplex virus type 1 in the gene encoding the major DNA-binding protein, ICP8, a mutant, d61, that grew efficiently in ICP8-expressing Vero cells but not in normal Vero cells was isolated (P. K. Orberg and P. A. Schaffer, J. Virol. 61:1136-1146, 1987). d61 was derived by cotransfection of ICP8-expressing Vero cells with infectious wild-type viral DNA and a plasmid, pDX, that contains an engineered 780-base-pair (bp) deletion in the ICP8 gene, as well as a spontaneous -55-bp deletion in OriL. Gel electrophoresis and Southern blot analysis indicated that d61 DNA carried both deletions present in pDX. The ability of d61 to replicate despite the deletion in OriL suggested that a functional OriL is not essential for virus replication in vitro. Because d61 harbored two mutations, a second mutant, ts+7, with a deletion in oriL-associated sequences and an intact ICP8 gene was constructed. Both d61 and ts+7 replicated efficiently in their respective permissive host cells, although their yields were slightly lower than those of control viruses with intact oriL sequences. -
Foamy Virus Assembly with Emphasis on Pol Encapsidation
Viruses 2013, 5, 886-900; doi:10.3390/v5030886 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Foamy Virus Assembly with Emphasis on Pol Encapsidation Eun-Gyung Lee 1, Carolyn R. Stenbak 2 and Maxine L. Linial 1,* 1 Fred Hutchinson Cancer Research Center, Basic Sciences Division; 1100 Fairview Avenue North, Seattle, WA 98109, USA; E-Mails: [email protected] (EGL); [email protected] (MLL) 2 Seattle University, Biology Department; 901 12th Avenue, Seattle, WA 98122, USA; E-Mail: [email protected] * Authors to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-206- 667-4442; Fax: +1-206-667-5939 Received: 31 January 2013; in revised form: 11 March 2013 / Accepted: 14 March 2013 / Published: 20 March 2013 Abstract: Foamy viruses (FVs) differ from all other genera of retroviruses (orthoretroviruses) in many aspects of viral replication. In this review, we discuss FV assembly, with special emphasis on Pol incorporation. FV assembly takes place intracellularly, near the pericentriolar region, at a site similar to that used by betaretroviruses. The regions of Gag, Pol and genomic RNA required for viral assembly are described. In contrast to orthoretroviral Pol, which is synthesized as a Gag-Pol fusion protein and packaged through Gag-Gag interactions, FV Pol is synthesized from a spliced mRNA lacking all Gag sequences. Thus, encapsidation of FV Pol requires a different mechanism. We detail how WT Pol lacking Gag sequences is incorporated into virus particles. In addition, a mutant in which Pol is expressed as an orthoretroviral-like Gag-Pol fusion protein is discussed. -
Viroporins: Structures and Functions Beyond Cell Membrane Permeabilization
Editorial Viroporins: Structures and Functions beyond Cell Membrane Permeabilization José Luis Nieva 1,* and Luis Carrasco 2,* Received: 17 September 2015 ; Accepted: 21 September 2015 ; Published: 29 September 2015 Academic Editor: Eric O. Freed 1 Biophysics Unit (CSIC, UPV/EHU) and Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain 2 Centro de Biología Molecular Severo Ochoa (CSIC, UAM), c/Nicolás Cabrera, 1, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain * Correspondence: [email protected] (J.L.N.); [email protected] (L.C.); Tel.: +34-94-601-3353 (J.L.N.); +34-91-497-8450 (L.C.) Viroporins represent an interesting group of viral proteins that exhibit two sets of functions. First, they participate in several viral processes that are necessary for efficient production of virus progeny. Besides, viroporins interfere with a number of cellular functions, thus contributing to viral cytopathogenicity. Twenty years have elapsed from the first review on viroporins [1]; since then several reviews have covered the advances on viroporin structure and functioning [2–8]. This Special Issue updates and revises new emerging roles of viroporins, highlighting their potential use as antiviral targets and in vaccine development. Viroporin structure. Viroporins are usually short proteins with at least one hydrophobic amphipathic helix. Homo-oligomerization is achieved by helix–helix interactions in membranes rendering higher order structures, forming aqueous pores. Progress in viroporin structures during the last 2–3 years has in some instances provided a detailed knowledge of their functional architecture, including the fine definition of binding sites for effective inhibitors. -
How Influenza Virus Uses Host Cell Pathways During Uncoating
cells Review How Influenza Virus Uses Host Cell Pathways during Uncoating Etori Aguiar Moreira 1 , Yohei Yamauchi 2 and Patrick Matthias 1,3,* 1 Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; [email protected] 2 Faculty of Life Sciences, School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK; [email protected] 3 Faculty of Sciences, University of Basel, 4031 Basel, Switzerland * Correspondence: [email protected] Abstract: Influenza is a zoonotic respiratory disease of major public health interest due to its pan- demic potential, and a threat to animals and the human population. The influenza A virus genome consists of eight single-stranded RNA segments sequestered within a protein capsid and a lipid bilayer envelope. During host cell entry, cellular cues contribute to viral conformational changes that promote critical events such as fusion with late endosomes, capsid uncoating and viral genome release into the cytosol. In this focused review, we concisely describe the virus infection cycle and highlight the recent findings of host cell pathways and cytosolic proteins that assist influenza uncoating during host cell entry. Keywords: influenza; capsid uncoating; HDAC6; ubiquitin; EPS8; TNPO1; pandemic; M1; virus– host interaction Citation: Moreira, E.A.; Yamauchi, Y.; Matthias, P. How Influenza Virus Uses Host Cell Pathways during 1. Introduction Uncoating. Cells 2021, 10, 1722. Viruses are microscopic parasites that, unable to self-replicate, subvert a host cell https://doi.org/10.3390/ for their replication and propagation. Despite their apparent simplicity, they can cause cells10071722 severe diseases and even pose pandemic threats [1–3]. -
Opportunistic Intruders: How Viruses Orchestrate ER Functions to Infect Cells
REVIEWS Opportunistic intruders: how viruses orchestrate ER functions to infect cells Madhu Sudhan Ravindran*, Parikshit Bagchi*, Corey Nathaniel Cunningham and Billy Tsai Abstract | Viruses subvert the functions of their host cells to replicate and form new viral progeny. The endoplasmic reticulum (ER) has been identified as a central organelle that governs the intracellular interplay between viruses and hosts. In this Review, we analyse how viruses from vastly different families converge on this unique intracellular organelle during infection, co‑opting some of the endogenous functions of the ER to promote distinct steps of the viral life cycle from entry and replication to assembly and egress. The ER can act as the common denominator during infection for diverse virus families, thereby providing a shared principle that underlies the apparent complexity of relationships between viruses and host cells. As a plethora of information illuminating the molecular and cellular basis of virus–ER interactions has become available, these insights may lead to the development of crucial therapeutic agents. Morphogenesis Viruses have evolved sophisticated strategies to establish The ER is a membranous system consisting of the The process by which a virus infection. Some viruses bind to cellular receptors and outer nuclear envelope that is contiguous with an intri‑ particle changes its shape and initiate entry, whereas others hijack cellular factors that cate network of tubules and sheets1, which are shaped by structure. disassemble the virus particle to facilitate entry. After resident factors in the ER2–4. The morphology of the ER SEC61 translocation delivering the viral genetic material into the host cell and is highly dynamic and experiences constant structural channel the translation of the viral genes, the resulting proteins rearrangements, enabling the ER to carry out a myriad An endoplasmic reticulum either become part of a new virus particle (or particles) of functions5. -
Assembly Lecture 11 Biology W3310/4310 Virology Spring 2014
Assembly Lecture 11 Biology W3310/4310 Virology Spring 2014 “Anatomy is des.ny.” --SIGMUND FREUD All virions complete a common set of assembly reac3ons * common to all viruses common to many viruses ©Principles of Virology, ASM Press The structure of a virus parcle determines how it is formed ©Principles of Virology, ASM Press Assembly is dependent on host cell machinery • Cellular chaperones • Transport systems • Secretory pathway • Nuclear import and export machinery Concentrang components for assembly: Nothing happens fast in dilute solu1ons • Viral components oSen visible by light microscopy (‘factories’ or ‘inclusions’) • Concentrate proteins on internal membranes (poliovirus) • Negri bodies (rabies virus) Viral proteins have ‘addresses’ built into their structure • Membrane targeYng: Signal sequences, fa\y acid modificaons • Membrane retenYon signals • Nuclear localizaYon sequences (NLS) • Nuclear export signals 414 Localiza3on of viral proteins to the nucleus CHAPTER 12 Golgi apparatus Ribosome Rough endoplasmic reticulum Plasma membrane Py(VP1) + VP2/3 Ad hexon + 5 100 kDa Nuclear envelope: Outer nuclear membrane Inner nuclear membrane Nucleus Nuclear pore complex Mitochondrion Cytoskeleton: Influenza virus NP Intermediate filament Microtubule Actin filament bundle Extracellular matrix ©Principles of Virology, ASM Press Figure 12.1 Localization of viral proteins to the nucleus. The nucleus and major membrane-bound compartments of the cytoplasm, as well as components of the cytoskeleton, are illustrated schematically and not to scale. Viral proteins destined for the nucleus are synthesized by cytoplasmic polyribosomes, as illustrated for the infl uenza virus NP protein. They engage with the cytoplasmic face of the nuclear pore complex and are translocated into the nucleus by the protein import machinery of the host cell. -
(Infected Cell Protein 8) of Herpes Simplex Virus L*
THEJOURNAL OF BIOLOGICAL CHEMISTRY Vol. 262, No. 9, Issue of March 25, pp. 4260-4266, 1987 0 1987 by The American Society of Biological Chemists, Inc Printed in U.S. A. Interaction between theDNA Polymerase and Single-stranded DNA- binding Protein (Infected Cell Protein 8) of Herpes Simplex Virus l* (Received for publication, September 22, 1986) Michael E. O’DonnellS, Per EliasQ,Barbara E. Funnellll, and I. R. Lehman From the Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305 The herpes virus-encoded DNA replication protein, ICP8 completely inhibits replication of singly primed ssDNA infected cell protein 8 (ICPS), binds specifically to templates by the herpespolymerase. On the other hand, ICP8 single-stranded DNA with a stoichiometry of one ICPS strongly stimulates replication of duplex DNA. It does so, molecule/l2 nucleotides. In the absence of single- however, onlyin the presence of anuclear extract from stranded DNA, it assembles into long filamentous herpes-infected cells. structures. Binding of ICPS inhibits DNA synthesis by the herpes-induced DNA polymerase on singly primed EXPERIMENTALPROCEDURES single-stranded DNA circles. In contrast, ICPS greatly Materials-DNase I and venom phosphodiesterase were obtained stimulates replication of circular duplex DNA by the from Worthington. The syntheticoligodeoxynucleotide (44-mer) was polymerase. Stimulation occurs only in the presence of synthesized by the solid-phase coupling of protected phosphoramidate a nuclear extract from herpes-infected cells. Appear- nucleoside derivatives (11).3H-Labeled #X ssDNA was a gift from ance of the stimulatory activity in nuclear extracts Dr. R. Bryant (this department). pMOB45 (10.5 kilobases) linear coincides closely with the time of appearance of her- duplex plasmid DNA was a gift from Dr. -
Hepatitis C Virus P7—A Viroporin Crucial for Virus Assembly and an Emerging Target for Antiviral Therapy
Viruses 2010, 2, 2078-2095; doi:10.3390/v2092078 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Hepatitis C Virus P7—A Viroporin Crucial for Virus Assembly and an Emerging Target for Antiviral Therapy Eike Steinmann and Thomas Pietschmann * TWINCORE †, Division of Experimental Virology, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625 Hannover, Germany; E-Mail: [email protected] † TWINCORE is a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI). * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +49-511-220027-130; Fax: +49-511-220027-139. Received: 22 July 2010; in revised form: 2 September 2010 / Accepted: 6 September 2010 / Published: 27 September 2010 Abstract: The hepatitis C virus (HCV), a hepatotropic plus-strand RNA virus of the family Flaviviridae, encodes a set of 10 viral proteins. These viral factors act in concert with host proteins to mediate virus entry, and to coordinate RNA replication and virus production. Recent evidence has highlighted the complexity of HCV assembly, which not only involves viral structural proteins but also relies on host factors important for lipoprotein synthesis, and a number of viral assembly co-factors. The latter include the integral membrane protein p7, which oligomerizes and forms cation-selective pores. Based on these properties, p7 was included into the family of viroporins comprising viral proteins from multiple virus families which share the ability to manipulate membrane permeability for ions and to facilitate virus production. Although the precise mechanism as to how p7 and its ion channel function contributes to virus production is still elusive, recent structural and functional studies have revealed a number of intriguing new facets that should guide future efforts to dissect the role and function of p7 in the viral replication cycle. -
Presentation by Class I MHC Molecules Requires Cytoplasmic
Hepatitis C Virus Envelope Glycoprotein E1 Originates in the Endoplasmic Reticulum and Requires Cytoplasmic Processing for Presentation by Class I MHC Molecules This information is current as of September 26, 2021. Mark Selby, Ann Erickson, Christine Dong, Stewart Cooper, Peter Parham, Michael Houghton and Christopher M. Walker J Immunol 1999; 162:669-676; ; http://www.jimmunol.org/content/162/2/669 Downloaded from References This article cites 45 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/162/2/669.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 26, 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 © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Hepatitis C Virus Envelope Glycoprotein E1 Originates in the Endoplasmic Reticulum and Requires Cytoplasmic Processing for Presentation by Class I MHC Molecules1 Mark Selby,* Ann Erickson,* Christine Dong,* Stewart Cooper,† Peter Parham,† Michael Houghton,* and Christopher M.