Hepatitis C virus induces oxidation and degradation of apolipoprotein B to enhance lipid accumulation and promote viral production

Author summaryHepatitis C virus (HCV) infection induces the degradation of apolipoprotein B (ApoB), which is the primary apolipoprotein in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Impaired production and secretion of ApoB-containing lipoprotein is associated with an increase in hepatic steatosis. Thus, ApoB degradation might contribute to HCV infection-induced fatty liver. Here, we found that ApoB was not degraded through endoplasmic reticulum-associated degradation (ERAD) or autophagy, as reported previously. Instead, HCV infection induced ApoB oxidation through oxidative stress, and oxidatively damaged ApoB could be recognized and directly degraded by the 20S proteasome. We also found that ApoB was retrotranslocated from the endoplasmic reticulum (ER) to lipid droplets (LDs) for degradation. Through overexpression of ApoB-50, which can mediate the assembly and secretion of LDL and VLDL, we confirmed that ApoB degradation contributed to hepatocellular lipid accumulation induced by HCV infection. Additionally, expression of ApoB-50 impaired HCV production due to the observed decrease in lipid accumulation. In this study, we identified new mechanisms of ApoB degradation and HCV-induced lipid accumulation, and our findings might facilitate the development of novel therapeutic strategies for HCV infection-induced fatty liver. Hepatitis C virus (HCV) infection induces the degradation and decreases the secretion of apolipoprotein B (ApoB). Impaired production and secretion of ApoB-containing lipoprotein is associated with an increase in hepatic steatosis. Therefore, HCV infection-induced degradation of ApoB may contribute to hepatic steatosis and decreased lipoprotein secretion, but the mechanism of HCV infection-induced ApoB degradation has not been completely elucidated. In this study, we found that the ApoB level in HCV-infected cells was regulated by proteasome-associated degradation but not autophagic degradation. ApoB was degraded by the 20S proteasome in a ubiquitin-independent manner. HCV induced the oxidation of ApoB via oxidative stress, and oxidized ApoB was recognized by the PSMA5 and PSMA6 subunits of the 20S proteasome for degradation. Further study showed that ApoB was degraded at endoplasmic reticulum (ER)-associated lipid droplets (LDs) and that the retrotranslocation and degradation of ApoB required Derlin-1 but not gp78 or p97. Moreover, we found that knockdown of ApoB before infection increased the cellular lipid content and enhanced HCV assembly. Overexpression of ApoB-50 inhibited lipid accumulation and repressed viral assembly in HCV-infected cells. Our study reveals a novel mechanism of ApoB degradation and lipid accumulation during HCV infection and might suggest new therapeutic strategies for hepatic steatosis.