ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production

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.
Author Summary HCV replication is linked to the host lipid metabolism, and virions are secreted as lipo-viro-particles whose density, size and biochemical content resemble VLDL. HCV assembles close to lipid droplets and is released via the secretory pathway, but it remains unclear how it accesses the VLDL assembly pathway. In this study, we identified ABHD5 as a new host factor supporting HCV assembly and release. ABHD5 is a lipid droplet-associated lipase cofactor. In hepatocytes, ABHD5 was proposed to promote the recruitment of triglycerides from cytosolic towards luminal lipid droplets by mediating a cycle of phospholipid hydrolysis/re-esterification. Our data suggest that this ABHD5-dependent lipid transfer is not only required for VLDL maturation, but also for HCV assembly and virion release, indicating that lipid remodelling impacts on both assembly and virus transport. Finally, ABHD5 is associated with the Chanarin-Dorfman syndrome, a rare human genetic lipid metabolism disorder. We found that the Chanarin-Dorfman syndrome mutants were unable to support HCV assembly, pointing at a new host polymorphism that could determine susceptibility to HCV infection. Altogether, our results establish a new link between HCV, VLDL assembly and lipid remodeling pathways and open new possibilities to study the etiology of the liver manifestations of the Chanarin-Dorfman syndrome.