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Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1

Abstract

Hepatitis C virus (HCV) infection is closely tied to the lipid metabolism of liver cells. Here we identify the triglyceride-synthesizing enzyme diacylglycerol acyltransferase-1 (DGAT1) as a key host factor for HCV infection. DGAT1 interacts with the viral nucleocapsid core and is required for the trafficking of core to lipid droplets. Inhibition of DGAT1 activity or RNAi-mediated knockdown of DGAT1 severely impairs infectious virion production, implicating DGAT1 as a new target for antiviral therapy.

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Figure 1: DGAT1 activity is necessary for HCV particle assembly at lipid droplets.
Figure 2: Specific interaction of the HCV core protein with DGAT1.

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Acknowledgements

We thank E. Yen (University of North Carolina–Chapel Hill) for Sf9 cell lysates, R. Bartenschlager (University of Heidelberg) for Luc-Jc1, Luc-JFH1, Jc1 constructs and Huh7 Lunet cells, C.M. Rice (Rockefeller University) for Huh7.5 cells, F.V. Chisari (Scripps Research Institute) for Huh7.5.1 cells, J. McLauchlan (Medical Research Council Virology Unit) for JFH1, JFH1 GND and JFH1ΔE1E2, T. Wakita (National Institute of Infectious Diseases, Japan) for the JFH1 construct and M. Spindler (Gladstone Institute of Cardiovascular Disease) for the pSicoRMS. We thank the members of the Ott and Farese laboratories for support. This work was supported by funds from the Gladstone Institutes, the Hellman Family Foundation (M.O.) and the US National Institutes of Health (R03 AI069090 (M.O.); R01 DK056084 (R.V.F. Jr.); P30 DK026743 (University of California–San Francisco Liver Center)). We gratefully acknowledge support through fellowships from the Human Frontiers Science Program (E.H.), the Agence nationale de recherches sur le sida et les hépatites virales (C. Hernandez and A.C.), and a training grant from the US National Institute of Diabetes and Digestive and Kidney Diseases (C. Harris).

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Authors and Affiliations

Authors

Contributions

E.H. designed, performed and analyzed most of the experiments and wrote the manuscript. C. Harris and R.V.F. Jr. provided the DGAT1 inhibitor. C. Harris also performed DGAT activity assays, analyzed data and edited the manuscript. C. Hernandez and A.C. performed the experiments in human primary hepatocytes. K.K. constructed the DGAT1 mutants and performed some of the immunoprecipitation experiments. A.R.R., R.V.F. Jr. and M.O. supervised this work, analyzed data and edited (A.R.R. and R.V.F.) or wrote (M.O.) the manuscript.

Corresponding author

Correspondence to Melanie Ott.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7 and Supplementary Methods (PDF 1396 kb)

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Herker, E., Harris, C., Hernandez, C. et al. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 16, 1295–1298 (2010). https://doi.org/10.1038/nm.2238

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