Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation

Jin Ye, Chunfu Wang, Rhea Sumpter, Michael S. Brown, Joseph L. Goldstein, Michael Gale

Research output: Contribution to journalArticle

300 Citations (Scopus)

Abstract

Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with Iovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to Iovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.

Original languageEnglish (US)
Pages (from-to)15865-15870
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number26
DOIs
StatePublished - Dec 23 2003

Fingerprint

Protein Prenylation
Virus Replication
Hepacivirus
RNA
Prenylation
Virus Assembly
Transferases
Proteins
Farnesol
Intracellular Membranes
Viral Proteins
Virus Diseases
Coenzyme A
Hepatocellular Carcinoma
Cultured Cells
Oxidoreductases
Genome
Membranes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{4960531a8e9c4008b888b551a2957aa6,
title = "Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation",
abstract = "Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with Iovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to Iovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.",
author = "Jin Ye and Chunfu Wang and Rhea Sumpter and Brown, {Michael S.} and Goldstein, {Joseph L.} and Michael Gale",
year = "2003",
month = "12",
day = "23",
doi = "10.1073/pnas.2237238100",
language = "English (US)",
volume = "100",
pages = "15865--15870",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "26",

}

TY - JOUR

T1 - Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation

AU - Ye, Jin

AU - Wang, Chunfu

AU - Sumpter, Rhea

AU - Brown, Michael S.

AU - Goldstein, Joseph L.

AU - Gale, Michael

PY - 2003/12/23

Y1 - 2003/12/23

N2 - Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with Iovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to Iovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.

AB - Hepatitis C virus (HCV) RNA replication depends on viral protein association with intracellular membranes, but the influence of membrane composition on viral replication is unclear. We report that HCV RNA replication and assembly of the viral replication complex require geranylgeranylation of one or more host proteins. In cultured hepatoma cells, HCV RNA replication was disrupted by treatment with Iovastatin, an inhibitor of 3-hydroxy-3-methyglutaryl CoA reductase, or with an inhibitor of protein geranylgeranyl transferase I, each of which induced the dissolution of the HCV replication complex. Viral replication was not affected by treatment of cells with an inhibitor of farnesyl transferase. When added to Iovastatin-treated cells, geranylgeraniol, but not farnesol, restored replication complex assembly and viral replication. Inasmuch as the HCV genome does not encode a canonical geranylgeranylated protein, the data suggest the involvement of a geranylgeranylated host protein in HCV replication. Inhibition of its geranylgeranylation affords a therapeutic strategy for treatment of HCV infection.

UR - http://www.scopus.com/inward/record.url?scp=0346103657&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0346103657&partnerID=8YFLogxK

U2 - 10.1073/pnas.2237238100

DO - 10.1073/pnas.2237238100

M3 - Article

C2 - 14668447

AN - SCOPUS:0346103657

VL - 100

SP - 15865

EP - 15870

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 26

ER -