Abstract
Hepatitis C virus (HCV) particles closely mimic human very-low-density lipoproteins (VLDL) to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (α/β hydrolase domain containing protein 5, also known as CGI-58) as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis.
Highlights
Hepatitis C virus (HCV) chronically infects around 146 million people worldwide [1] and the associated cases of end-stage liver disease constitute a major indication for liver transplantation [2]
HCV replication is linked to the host lipid metabolism, and virions are secreted as lipoviro-particles whose density, size and biochemical content resemble very low density lipoproteins (VLDL)
We identified ABHD5 as a new host factor supporting HCV assembly and release
Summary
HCV chronically infects around 146 million people worldwide [1] and the associated cases of end-stage liver disease constitute a major indication for liver transplantation [2]. The virion strikingly resembles very low density lipoproteins (VLDL) with its unusually low buoyant density, its association with apolipoproteins and peculiar lipid content [4,5,6,7,8] This mimicry enables the use of lipid receptors in the virus entry process and facilitates the homing to liver cells as well as antibody escape [9]. In the course of virus assembly HCV modulates lipid droplets (LD), the principal cellular lipid storage organelles, by deposition of viral components and manipulation of LD motility [10,11] This process is probably initiated by the viral core protein, which uses DGAT1 to translocate from the ER membrane onto the lipid droplet (LD) surface [12]. The mechanisms that mediate the loading of HCV particles with apolipoproteins and VLDL lipids are poorly understood
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