ZEB2 inhibits HBV transcription and replication by targeting its core promoter.

Qiao He,Wanyu Li,Ying Huang,Weixian Chen,Juan Chen,Qin Hu,Jihua Ren,Yecai Huang

doi:10.18632/oncotarget.7435

Abstract

Hepatitis B virus (HBV) infection is a major cause of liver diseases, especially liver cirrhosis and hepatocellular carcinoma. However, the interaction between host and HBV has not been fully elucidated. ZEB2 is a Smad-interacting, multi-zinc finger protein that acts as a transcription factor or repressor for several signaling pathways. This study found that the expression of ZEB2 was decreased in HBV-expressing cells. Overexpression of ZEB2 inhibited HBV DNA replicative intermediates, 3.5kb mRNA, core protein level, and the secretion of HBsAg and HBeAg. In contrast, ZEB2 knockdown promoted HBV replication. Furthermore, ZEB2 could bind to HBV core promoter and inhibit its promoter activity. Mutation at the ZEB2 binding site in HBV core promoter eradicated ZEB2-mediated inhibition of HBV replication. This study identifies ZEB2 as a novel host restriction factor that inhibits HBV replication in hepatocytes. These data may shed light on development of new antiviral strategies.

Highlights

Hepatitis B virus (HBV) infection leads to a wide spectrum of liver diseases, including acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC)
To identify a potential relationship between HBV replication and the transcription factor ZEB2, the study first examined expression of ZEB2 in HepG2, HepG2.2.15—which is another HepG2 cell line that stably expresses HBV, and human hepatoma HepG2 cells transiently transfected with HBV expressing plasmid pCH-9/3091, which contains a 1.1-unit length HBV genome driven by CMV promoter
The present study further examined ZEB2 expression in the HepAD38 cell line, in which HBV replication can be regulated by tetracycline

Summary

Introduction

HBV infection leads to a wide spectrum of liver diseases, including acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). 2 billion people are infected with HBV, and more than 350 million are chronic carriers [1]. HBV infection causes more than 600,000 deaths per year [2]. Nucleoside analogues (NA) and alpha interferon (IFN-α) are the major therapies for HBV patients. Long-term treatment with both NA and IFN-α may have drawbacks, including drug-resistant virus mutations and other side effects [3, 4]. Understanding of the molecular mechanism that determines HBV replication and pathogenesis is urgently needed

Methods

Results

Conclusion