4 years ago

N-Myc Downstream-Regulated Gene 1 Restricts Hepatitis C Virus Propagation by Regulating Lipid Droplet Biogenesis and Viral Assembly.

Cameron J Schweitzer, T Jake Liang, Audrey Boyer, Fang Zhang, Kristin Valdez, Maggie Cam
Host cells harbor various intrinsic mechanisms to restrict viral infections as a first line of antiviral defense. Viruses have evolved various countermeasures against these antiviral mechanisms. Here we show that N-Myc Downstream-Reguated Gene 1 (NDRG1) limits productive HCV infection by inhibiting viral assembly. Interestingly, HCV infection down-regulates NDRG1 protein and mRNA expression. Loss of NDRG1 increases the size and number of lipid droplets, which are the sites of HCV assembly. HCV suppresses NDRG1 expression by up-regulating MYC, which directly inhibits the transcription of NDRG1 Up-regulation of MYC also leads to reduced expression of NDRG1-specific kinase SGK1, resulting in markedly diminished phosphorylation of NDRG1. Knockdown of MYC during HCV infection rescues NDRG1 expression and phosphorylation, suggesting that MYC regulates NDRG1 at both transcriptional and post-translational levels. Overall, our results suggest that NDRG1 restricts HCV assembly by limiting lipid droplet formation. HCV counteracts this intrinsic antiviral mechanism by down-regulating NDRG1 via a MYC-dependent mechanism.IMPORTANCE Hepatitis C virus (HCV) is an enveloped single-stranded RNA virus that targets hepatocytes in the liver. HCV is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma and estimates suggest a global prevalence of 2.35%. Up to 80% of acutely infected individuals will develop chronic infection and as many as 5% eventually progress to liver cancer. Understanding of the mechanisms behind virus-host interaction and viral carcinogenesis is still lacking. The significance of our research is that it identifies a previously unknown relationship between HCV and a known tumor-associated gene. Further our data point to a new role for this gene in the liver and lipid metabolism. Thus HCV infection serves as a great biological model to advance our knowledge of liver functions and the development of liver cancer.

Publisher URL: http://doi.org/10.1128/JVI.01166-17

DOI: 10.1128/JVI.01166-17

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