Modulation of fatty acid synthase enzyme activity and expression during hepatitis C virus replication

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DOIResolve DOI: http://doi.org/10.1016/j.chembiol.2013.03.014
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TypeArticle
Journal titleChemistry and Biology
ISSN1074-5521
Volume20
Issue4
Pages570582; # of pages: 13
AbstractThe hepatitis C virus (HCV) induces alterations of host cells to facilitate its life cycle. Fatty acid synthase (FASN) is a multidomain enzyme that plays a key role in the biosynthesis of fatty acids and is upregulated during HCV infection. Herein, we applied activity-based protein profiling (ABPP) that allows for the identification of differentially active enzymes in complex proteomic samples, to study the changes in activity of FASN during HCV replication. For this purpose, we used an activity-based probe based on the FASN inhibitor Orlistat, and observed an increase in the activity of FASN in the presence of a subgenomic and a genomic HCV replicon as well as in chimeric SCID/Alb-uPA mice infected with HCV genotype 1a. To study the molecular basis for this increase in FASN activity, we overexpressed individual HCV proteins in Huh7 cells and observed increased expression and activity of FASN in the presence of core and NS4B, as measured by western blots and ABPP, respectively. Triglyceride levels were also elevated in accordance with FASN expression and activity. Lastly, immunofluorescence and ABPP imaging analyses demonstrated that while the abundance and activity of FASN increases significantly in the presence of HCV, its localization does not change. Together these data suggest that the HCV-induced production of fatty acids and neutral lipids is provided by an increase in FASN abundance and activity that is sufficient to allow HCV propagation without transporting FASN to the replication complexes.
Publication date
LanguageEnglish
AffiliationMedical Devices; National Research Council Canada
Peer reviewedYes
NPARC number21270392
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Record identifier2cf64c45-974d-483b-957d-7d1003fad928
Record created2014-02-06
Record modified2016-05-09
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