Efficient Hepatitis C Virus Particle Formation Requires Diacylglycerol Acyltransferase 1 (DGAT1)

Gladstone Institute of Virology and Immunology, University of California, San Francisco, USA.
Nature medicine (Impact Factor: 27.36). 10/2010; 16(11):1295-8. DOI: 10.1038/nm.2238
Source: PubMed


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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Available from: Katrin Kaehlcke, Mar 16, 2015
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    • "Interestingly, CK1-dependent NS5A hyperphosphorylation appears to recruit NS5A to low-density membrane fractions around cLDs, thus promoting interaction with core and nucleocapsid assembly (Masaki et al., 2014). Core recruitment to cLDs is influenced by cellular enzymes involved in LD homeostasis, including cytosolic phospholipase A2 (Menzel et al., 2012) and diacylglycerol acyltransferase-1 (Herker et al., 2010). The latter also binds to and recruits NS5A to cLDs, thus promoting core-NS5A interaction (Camus et al., 2013). "
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    ABSTRACT: Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Although highly potent direct-acting antiviral drugs to treat chronic hepatitis C have been approved recently, owing to their high costs and limited availability and a large number of undiagnosed infections, the burden of disease is expected to rise in the next few years. In addition, HCV is an excellent paradigm for understanding the tight link between a pathogen and host cell pathways, most notably lipid metabolism. HCV extensively remodels intracellular membranes to establish its cytoplasmic replication factory and also usurps components of the intercellular lipid transport system for production of infectious virus particles. Here, we review the molecular mechanisms of viral replicase function, cellular pathways employed during HCV replication factory biogenesis, and viral, as well as cellular, determinants of progeny virus production.
    Cell Host & Microbe 11/2014; 16(5):569-579. DOI:10.1016/j.chom.2014.10.008 · 12.33 Impact Factor
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    • "The establishment of fully permissive cell culture systems (HCVcc) [2], [3] revealed a close connection between host cell lipids and HCV replication at each step of the viral replication cycle reviewed in [4]. Interestingly, the cellular storage organelles of lipids, lipid droplets, emerged as putative viral assembly sites [5]–[7]. "
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    ABSTRACT: Cytosolic lipid droplets are central organelles in the Hepatitis C Virus (HCV) life cycle. The viral capsid protein core localizes to lipid droplets and initiates the production of viral particles at lipid droplet-associated ER membranes. Core is thought to encapsidate newly synthesized viral RNA and, through interaction with the two envelope proteins E1 and E2, bud into the ER lumen. Here, we visualized the spatial distribution of HCV structural proteins core and E2 in vicinity of small lipid droplets by three-color 3D super-resolution microscopy. We observed and analyzed small areas of colocalization between the two structural proteins in HCV-infected cells with a diameter of approximately 100 nm that might represent putative viral assembly sites.
    PLoS ONE 07/2014; 9(7):e102511. DOI:10.1371/journal.pone.0102511 · 3.23 Impact Factor
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    • "During infection, some nonstructural proteins of HCV, such as NS2, NS3, and NS5A and viral replication RNA complexes are recruited on the LD membrane surface.163 A critical role of DGAT1, the enzyme that synthesizes TGs in the ER, in recruiting the virus to LDs has been recently reported.165 DGAT1 would serve as a cellular hub for HCV core and NS5A proteins, guiding both onto the surface of the same subset of LDs. "
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    ABSTRACT: The main cells of the adipose tissue of animals, adipocytes, are characterized by the presence of large cytosolic lipid droplets (LDs), which store triglyceride (TG) and cholesterol. However, most cells have LDs and the ability to store lipids. LDs have a well-known central role in storage and provision of fatty acids and cholesterol. However, the complexity of the regulation of lipid metabolism on the surface of the LDs is still a matter of intense study. Beyond this role, a number of recent studies have suggested that LDs have major functions in other cellular processes, such as protein storage and degradation, and infection and immunity. Thus, our perception of LDs, from simple globules of fat to highly dynamic organelles of unexpected complexity, has been radically transformed. Here we compiled some recent evidence supporting the emerging view that LDs act as platforms connecting a number of relevant metabolic and cellular functions.
    Lipid Insights 05/2014; 7(1):7-16. DOI:10.4137/LPI.S11128
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