U.S. Department of Energy

Pacific Northwest National Laboratory

Systems virology identifies a mitochondrial fatty acid oxidation enzyme, dodecenoyl coenzyme A delta isomerase, required for hepatitis C virus replication and likely pathogenesis.

TitleSystems virology identifies a mitochondrial fatty acid oxidation enzyme, dodecenoyl coenzyme A delta isomerase, required for hepatitis C virus replication and likely pathogenesis.
Publication TypeJournal Article
Year of Publication2011
AuthorsRasmussen AL, Diamond DL, McDermott JE, Gao X, Metz TO, Matzke MM, Carter VS, Belisle SE, Korth MJ, Waters KM, Smith RD, Katze MG
JournalJ Virol
KeywordsBiopsy, Carbon-Carbon Double Bond Isomerases, Cell Line, Dodecenoyl-CoA Isomerase, Fatty Acids, Gene Silencing, Hepacivirus, Hepatocytes, Host-Pathogen Interactions, Humans, Liver, Mitochondria, Oxidation-Reduction, Proteome, Virus Replication
Abstract

We previously employed systems biology approaches to identify the mitochondrial fatty acid oxidation enzyme dodecenoyl coenzyme A delta isomerase (DCI) as a bottleneck protein controlling host metabolic reprogramming during hepatitis C virus (HCV) infection. Here we present the results of studies confirming the importance of DCI to HCV pathogenesis. Computational models incorporating proteomic data from HCV patient liver biopsy specimens recapitulated our original predictions regarding DCI and link HCV-associated alterations in cellular metabolism and liver disease progression. HCV growth and RNA replication in hepatoma cell lines stably expressing DCI-targeting short hairpin RNA (shRNA) were abrogated, indicating that DCI is required for productive infection. Pharmacologic inhibition of fatty acid oxidation also blocked HCV replication. Production of infectious HCV was restored by overexpression of an shRNA-resistant DCI allele. These findings demonstrate the utility of systems biology approaches to gain novel insight into the biology of HCV infection and identify novel, translationally relevant therapeutic targets.

DOI10.1128/JVI.05605-11
Alternate JournalJ. Virol.
PubMed ID21917952
PubMed Central IDPMC3209311
Grant List1P30DA01562501 / DA / NIDA NIH HHS / United States
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