Abstract
The role of hepatitis B virus (HBV) X protein (HBx) in the regulation of HBV replication remains controversial. In the present study, the role of HBx in regulating HBV replication was initially investigated in both HepG2 and Huh7 in vitro cell lines with a transient transfection system. Next, the regions of HBx responsible for transcriptional transactivation and promotion of HBV replication were mapped in an HBV replication mouse model by in vivo transfection of a series of HBx expression plasmids. In an in vitro setting, HBx deficiency had little effect on HBV replication in Huh7 cells, but impaired HBV replication in HepG2 cells. In an in vivo setting, HBx had a strong enhancing effect on HBV transcription and replication. For the C-terminal two-thirds of the protein (amino acids [aa] 51 to 154) was required for this function of HBx, and the regions spanning aa 52 to 72 and 88 to 154 were found to be important for the stimulatory function of HBx on HBV replication. In conclusion, the role of HBx in HBV replication regulation is affected by host cell type, and HBx has an important role in stimulating HBV transcription and replication in hepatocytes in vivo. Further, the transcriptional transactivation function of HBx may be crucial for its stimulatory effect on HBV transcription and replication.
Highlights
Chronic hepatitis B virus (HBV) infection is a worldwide health problem, and it has become one of the major causes of end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC) [1,2].In the past decade, the crucial role of HBV in hepatocarcinogenesis has been well established, but the mechanisms underlying how HBV induces malignant transformation of hepatocytes remains unclear [3].HBV X (HBx) is a 154-amino-acid (154-aa) multifunctional protein that has roles in gene transcription, cell proliferation, and apoptosis [4,5,6]
Our previous studies showed that HBx could augment HBV transcription and replication, as a mutant HBV genome with a defective X gene led to decreased levels of 3.5-kb HBV RNA and HBV replication intermediates; these decreases could be restored by either transient ectopic expression of HBx or stable HBx expression in HepG2 cells [10]
Our findings suggest that HBx can enhance HBV replication in HepG2 cells, but not in Huh7 cells
Summary
Chronic hepatitis B virus (HBV) infection is a worldwide health problem, and it has become one of the major causes of end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC) [1,2]. HBV X (HBx) is a 154-amino-acid (154-aa) multifunctional protein that has roles in gene transcription, cell proliferation, and apoptosis [4,5,6]. to 154) is required for this function of HBx, and the regions spanning aa to 65 and aa 88 to 154 are important for the transactivation or coactivation activities of HBx and its stimulatory function in HBV transcription and replication [16] All these experiments were performed in an in vitro system. We sought to verify roles of the transcriptional transactivation regions in the C-terminal transactivation domain of HBx in modulating the levels of HBV transcription and replication under physiological conditions in vivo
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