Lee Emily M, Alsagheir Ali, Wu Xianfang, Hammack Christy, McLauchlan John, Watanabe Noriyuki, Wakita Takaji, Kneteman Norman M, Douglas Donna N, Tang Hengli
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
J Virol. 2016 Mar 28;90(8):4174-85. doi: 10.1128/JVI.02891-15. Print 2016 Apr.
Individuals chronically infected with hepatitis C virus (HCV) commonly exhibit hepatic intracellular lipid accumulation, termed steatosis. HCV infection perturbs host lipid metabolism through both cellular and virus-induced mechanisms, with the viral core protein playing an important role in steatosis development. We have recently identified a liver protein, the cell death-inducing DFFA-like effector B (CIDEB), as an HCV entry host dependence factor that is downregulated by HCV infection in a cell culture model. In this study, we investigated the biological significance and molecular mechanism of this downregulation. HCV infection in a mouse model downregulated CIDEB in the liver tissue, and knockout of the CIDEB gene in a hepatoma cell line results in multiple aspects of lipid dysregulation that can contribute to hepatic steatosis, including reduced triglyceride secretion, lower lipidation of very-low-density lipoproteins, and increased lipid droplet (LD) stability. The potential link between CIDEB downregulation and steatosis is further supported by the requirement of the HCV core and its LD localization for CIDEB downregulation, which utilize a proteolytic cleavage event that is independent of the cellular proteasomal degradation of CIDEB.
Our data demonstrate that HCV infection of human hepatocytesin vitroandin vivoresults in CIDEB downregulation via a proteolytic cleavage event. Reduction of CIDEB protein levels by HCV or gene editing, in turn, leads to multiple aspects of lipid dysregulation, including LD stabilization. Consequently, CIDEB downregulation may contribute to HCV-induced hepatic steatosis.
慢性丙型肝炎病毒（HCV）感染者通常表现出肝内细胞内脂质蓄积，即脂肪变性。HCV感染通过细胞和病毒诱导的机制扰乱宿主脂质代谢，病毒核心蛋白在脂肪变性发展中起重要作用。我们最近在细胞培养模型中鉴定出一种肝脏蛋白，即细胞死亡诱导DFFA样效应蛋白B（CIDEB），它是HCV进入宿主的依赖因子，会被HCV感染下调。在本研究中，我们调查了这种下调的生物学意义和分子机制。小鼠模型中的HCV感染下调了肝组织中的CIDEB，而肝癌细胞系中CIDEB基因的敲除导致脂质调节异常的多个方面，这些异常可导致肝脂肪变性，包括甘油三酯分泌减少、极低密度脂蛋白的脂化降低以及脂滴（LD）稳定性增加。HCV核心蛋白及其在LD中的定位对CIDEB下调的需求进一步支持了CIDEB下调与脂肪变性之间的潜在联系，这种下调利用了一个蛋白水解切割事件，该事件独立于CIDEB的细胞蛋白酶体降解。
我们的数据表明，体外和体内人肝细胞的HCV感染通过蛋白水解切割事件导致CIDEB下调。反过来，HCV或基因编辑导致的CIDEB蛋白水平降低会导致脂质调节异常的多个方面，包括LD稳定。因此，CIDEB下调可能导致HCV诱导的肝脂肪变性。
