title: Systems virology identifies a mitochondrial fatty acid oxidation enzyme, dodecenoyl coenzyme A delta isomerase, required for hepatitis C virus replication and likely pathogenesis.
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.
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, Box 358070, Seattle, WA 98195, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Rasmussen
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Diamond
authors.forename: Jason E
authors.initials: JE
authors.lastname: McDermott
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Metz
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Matzke
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Carter
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Belisle
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Korth
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D001706:Biopsy; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism*; D002460:Cell Line; D064006:Dodecenoyl-CoA Isomerase; D005227:Fatty Acids / Q000378:metabolism; D020868:Gene Silencing; D016174:Hepacivirus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000201:enzymology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology*; D010084:Oxidation-Reduction; D020543:Proteome; D014779:Virus Replication
chemical_list: D005227:Fatty Acids; D020543:Proteome; D019748:Carbon-Carbon Double Bond Isomerases; D064006:Dodecenoyl-CoA Isomerase; C576298:ECI1 protein, human; C119738:ECI2 protein, human