Home LiteratureArticle Details
PMID: 12719597 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Amphipathic helix-dependent localization of NS5A mediates hepatitis C virus RNA replication.

Journal of virology ·Vol. 77 ·No. 10 ·2003-05-00 ·Pages 6055-61

Elazar M, Cheong KH, Liu P, Greenberg HB, Rice CM, Glenn JS

Abstract

We identified an N-terminal amphipathic helix (AH) in one of hepatitis C virus (HCV)'s nonstructural proteins, NS5A. This AH is necessary and sufficient for membrane localization and is conserved across isolates. Genetically disrupting the AH impairs HCV replication. Moreover, an AH peptide-mimic inhibits the membrane association of NS5A in a dose-dependent manner. These results have exciting implications for the HCV life cycle and novel antiviral strategies.

MeSH Terms
Amino Acid Sequence Cell Line Cell Membrane/metabolism,virology Conserved Sequence Gene Expression Regulation, Viral Hepacivirus/genetics,physiology Humans Peptides/chemical synthesis,chemistry RNA, Viral/biosynthesis Viral Nonstructural Proteins/chemistry,genetics,metabolism Virus Replication
Chemicals
NS-5 protein, hepatitis C virus Peptides RNA, Viral Viral Nonstructural Proteins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Elazar Menashe
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California 94305, USA.
Cheong Kwang Ho
Liu Ping
Greenberg Harry B
Rice Charles M
Glenn Jeffrey S
References (44)
44 references, click to expand
  1. Structural and functional characterization of the poliovirus replication complex.
    J Virol. 1992 May;66(5):2740-7 PMID: 1313898
  2. Amphipathic helix motif: classes and properties.
    Proteins. 1990;8(2):103-17 PMID: 2235991
  3. Expression and identification of hepatitis C virus polyprotein cleavage products.
    J Virol. 1993 Mar;67(3):1385-95 PMID: 7679746
  4. Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome.
    J Gen Virol. 1993 Jun;74 ( Pt 6):1103-13 PMID: 8389800
  5. Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus.
    Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10773-7 PMID: 7504283
  6. Studies of a putative amphipathic helix in the N-terminus of poliovirus protein 2C.
    Virology. 1994 Feb 15;199(1):188-99 PMID: 8116242
  7. Sorting and retrieval between the endoplasmic reticulum and Golgi apparatus.
    Curr Opin Cell Biol. 1995 Aug;7(4):530-5 PMID: 7495573
  8. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection.
    N Engl J Med. 1996 Jan 11;334(2):77-81 PMID: 8531962
  9. Characterization of the nuclear localization signal and subcellular distribution of hepatitis C virus nonstructural protein NS5A.
    Gene. 1996 Dec 5;182(1-2):203-11 PMID: 8982089
  10. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein.
    Virology. 1997 Apr 14;230(2):217-27 PMID: 9143277
  11. Poliovirus 2C protein determinants of membrane binding and rearrangements in mammalian cells.
    J Virol. 1997 Dec;71(12):8962-72 PMID: 9371552
  12. Membrane association and RNA binding of recombinant hepatitis A virus protein 2C.
    Arch Virol. 1998;143(5):931-44 PMID: 9645199
  13. Continuous human cell lines inducibly expressing hepatitis C virus structural and nonstructural proteins.
    Hepatology. 1998 Jul;28(1):192-201 PMID: 9657112
  14. The green fluorescent protein.
    Annu Rev Biochem. 1998;67:509-44 PMID: 9759496
  15. Use of a prenylation inhibitor as a novel antiviral agent.
    J Virol. 1998 Nov;72(11):9303-6 PMID: 9765479
  16. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.
    N Engl J Med. 1998 Nov 19;339(21):1485-92 PMID: 9819446
  17. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.
    Science. 1999 Jul 2;285(5424):110-3 PMID: 10390360
  18. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
    N Engl J Med. 1999 Aug 19;341(8):556-62 PMID: 10451460
  19. Modulation of hepatitis C virus NS5A hyperphosphorylation by nonstructural proteins NS3, NS4A, and NS4B.
    J Virol. 1999 Sep;73(9):7138-46 PMID: 10438800
  20. Subcellular localization of hepatitis C viral proteins in mammalian cells.
    Arch Virol. 1999;144(2):329-43 PMID: 10470257
  21. Hepatitis C virus RNA polymerase and NS5A complex with a SNARE-like protein.
    Virology. 1999 Oct 10;263(1):30-41 PMID: 10544080
  22. Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties.
    Curr Top Microbiol Immunol. 2000;242:55-84 PMID: 10592656
  23. Identification of the endoplasmic reticulum targeting signal in vesicle-associated membrane proteins.
    J Biol Chem. 1999 Dec 24;274(52):36876-82 PMID: 10601239
  24. Pathogenesis, natural history, treatment, and prevention of hepatitis C.
    Ann Intern Med. 2000 Feb 15;132(4):296-305 PMID: 10681285
  25. Natural history of hepatitis C: its impact on clinical management.
    Hepatology. 2000 Apr;31(4):1014-8 PMID: 10733560
  26. Replication of hepatitis C virus.
    J Gen Virol. 2000 Jul;81(Pt 7):1631-48 PMID: 10859368
  27. Different properties of two isoforms of annexin XIII in MDCK cells.
    J Cell Sci. 2000 Jul;113 ( Pt 14):2607-18 PMID: 10862718
  28. Hepatitis C virus RNA codes for proteins and replicates: does it also trigger the interferon response?
    Semin Liver Dis. 2000;20(1):57-68 PMID: 10895432
  29. Remodeling the endoplasmic reticulum by poliovirus infection and by individual viral proteins: an autophagy-like origin for virus-induced vesicles.
    J Virol. 2000 Oct;74(19):8953-65 PMID: 10982339
  30. Nuclear localization and intramolecular cleavage of N-terminally deleted NS5A protein of hepatitis C virus.
    Virus Res. 2000 Sep 25;69(2):109-17 PMID: 11018280
  31. Peginterferon alfa-2a in patients with chronic hepatitis C.
    N Engl J Med. 2000 Dec 7;343(23):1666-72 PMID: 11106715
  32. Efficient initiation of HCV RNA replication in cell culture.
    Science. 2000 Dec 8;290(5498):1972-4 PMID: 11110665
  33. A human hepatoma cell line expressing hepatitis c virus nonstructural proteins tightly regulated by tetracycline.
    Biochem Biophys Res Commun. 2001 Mar 2;281(3):732-40 PMID: 11237719
  34. How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A.
    Virology. 2001 May 25;284(1):1-12 PMID: 11352662
  35. The hepatitis C virus nonstructural protein 4B is an integral endoplasmic reticulum membrane protein.
    Virology. 2001 May 25;284(1):70-81 PMID: 11352669
  36. Determinants for membrane association of the hepatitis C virus RNA-dependent RNA polymerase.
    J Biol Chem. 2001 Nov 23;276(47):44052-63 PMID: 11557752
  37. An amino-terminal amphipathic alpha-helix mediates membrane association of the hepatitis C virus nonstructural protein 5A.
    J Biol Chem. 2002 Mar 8;277(10):8130-9 PMID: 11744739
  38. Hepatitis C virus (HCV) NS5A binds RNA-dependent RNA polymerase (RdRP) NS5B and modulates RNA-dependent RNA polymerase activity.
    J Biol Chem. 2002 Mar 29;277(13):11149-55 PMID: 11801599
  39. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex.
    J Virol. 2002 Jun;76(12):5974-84 PMID: 12021330
  40. Association of foot-and-mouth disease virus replicase with RNA template and cytoplasmic membranes.
    J Gen Virol. 1974 May;23(2):213-8 PMID: 4364882
  41. Kinetics and location of poliovirus macromolecular synthesis in correlation to virus-induced cytopathology.
    Virology. 1980 Jan 30;100(2):390-9 PMID: 6243433
  42. Alphavirus RNA replicase is located on the cytoplasmic surface of endosomes and lysosomes.
    J Cell Biol. 1988 Dec;107(6 Pt 1):2075-86 PMID: 2904446
  43. In vitro-synthesized hepatitis delta virus RNA initiates genome replication in cultured cells.
    J Virol. 1990 Jun;64(6):3104-7 PMID: 2335830
  44. Molecular and ultrastructural analysis of heavy membrane fractions associated with the replication of Kunjin virus RNA.
    Arch Virol. 1992;125(1-4):177-91 PMID: 1322651
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
Published
2003-05-00
Pages
6055-61
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC154017
Subset
IM
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]