Chronic infection with the hepatitis C virus frequently induces steatosis, which is a significant risk factor for liver pathogenesis. Steatosis is characterized by the accumulation of lipid droplets in hepatocytes. The structural protein core of the virus induces lipid droplet formation and localizes on the surface of the lipid droplets. However, the precise molecular mechanisms for the core-induced formation of lipid droplets remain elusive. Recently, we showed that the expression of the core protein in yeast as a model system could induce lipid droplet formation. In this study, we probed the cellular factors responsible for the formation of core-induced lipid-droplets in yeast cells. We demonstrated that one of the enzymes responsible for triglyceride synthesis, a phospholipid:diacylglycerol acyltransferase (Lro1), is required for the core-induced lipid droplet formation. While core proteins inhibit Lro1 degradation and alter Lro1 localization, the characteristic localization of Lro1 adjacent to the lipid droplets appeared to be responsible for the core-induced lipid droplet formation. RNA virus genomes have evolved using high mutation rates to maintain their ability to replicate. Our observations suggest a functional relationship between the core protein with hepatocytes and yeast cells. The possible interactions between core proteins and the endoplasmic reticulum membrane affect the mobilization of specific proteins.
-Chronic infection with the hepatitis C virus (HCV) frequently induces steatosis, which is characterized by the accumulation of lipid droplets (LDs) in hepatocytes. Steatosis is a significant risk factor for liver cancer. The HCV structural protein core is distributed on the surface of the endoplasmic reticulum (ER) and in LDs, thereby increasing LD levels. In this work, we attempt to elucidate the effect of the core protein on LD generation using yeast cells. We found that the core localized to the cytosolic surface of the ER in yeast and is able to increase LD levels when overexpressed from an inducible GAL1 promoter for 3 hr. The effect of the core was conserved among three different HCV serotypes: 1b, 2a and 3a. While the ER stress inducer tunicamycin both elicited an unfolded stress response (UPR) and increased LD levels, the core did not induce the UPR. The RNA viral genome changes rapidly due to its high mutation rate in order to replicate under a variety of circumstances. Our observations suggest a functional analogy between core function in hepatocytes and in yeast cells and thus might be applicable to the screening of small molecules that impair the core-ER interaction.
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