Abstract
Hepatitis B virus (HBV) replication is controlled by four promoters (preS1, preS2, Cp, and Xp) and two enhancers (EnhI and EnhII). EnhII stimulates Cp activity to regulate the transcriptions of precore, core, polymerase, and pregenomic RNAs, and therefore, EnhII/Cp is essential for the regulation of HBV replication. This study revealed a distinct mechanism underlying the suppression of EnhII/Cp activation and HBV replication. On the one hand, the sex determining region Y box2 (SOX2), a transcription factor, is induced by HBV. On the other hand, SOX2, in turn, represses the expression levels of HBV RNAs, HBV core-associated DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg), thereby playing an inhibitory role during HBV replication. Further studies indicated that SOX2 bound to the EnhII/Cp DNA and repressed the promoter activation. With the deletion of the high mobility group (HMG) domain, SOX2 loses the ability to repress EnhII/Cp activation, viral RNA transcription, HBV core-associated DNA replication, HBsAg and HBeAg production, as well as fails to enter the nucleus, demonstrating that the HMG domain is required for the SOX2-mediated repression of HBV replication. Moreover, SOX2 represses HBsAg and HBeAg secretion in BALB/c mice sera, and attenuates HBV 3.5 kb RNA transcription and hepatitis B virus core protein (HBc) production in the liver tissues, demonstrating that SOX2 suppresses HBV replication in mice. Furthermore, the results revealed that the HMG domain was required for SOX2-mediated repression of HBV replication in the mice. Taken together, the above facts indicate that SOX2 acts as a new host restriction factor to repress HBV replication by binding to the viral EnhII/Cp and inhibiting the promoter activation through the HMG domain.
Highlights
Hepatitis B virus (HBV) had infected about 3 billion people worldwide, which led to 800,000 deaths per year [1,2]
The results from the dual-luciferase reporter assay showed that the activity of EnhII/Cp was significantly inhibited by sex determining region Y box2 (SOX2), SOX2 (1–540 nt), SOX2 (1–600 nt), and SOX2 (121–954 nt) (Figure 4B, lanes 2, and 4–6), attenuated by SOX2 (1–333 nt) (Figure 4B, lane 3), but not affected by SOX2 (334–954 nt), SOX2 (541–954 nt), and SOX2 (601–954 nt) (Figure 4B, lanes 7–9). These results indicated that the sequences from 121 nt to 333 nt of SOX2 containing the high mobility group (HMG) domain were required for SOX2-mediated repression of EnhII/Cp activity
The results revealed that the levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were significantly reduced by SOX2, but not by SOX2 ∆HMG (Figure 5A,B), suggesting that SOX2 represses the secretion of HBsAg and
Summary
Hepatitis B virus (HBV) had infected about 3 billion people worldwide, which led to 800,000 deaths per year [1,2]. SOX2 activates the expression of programmed death ligand-1 (PD-L1) through direct binding to the PD-L1 promoter in hepatoma cells. It was revealed that HBV could induce the production of cancer stem cells (CSCs)-related markers (CD133, CD117, and CD90) and CSCs-related genes (Klf, SOX2, Nanog, c-Myc, and Oct4) and facilitate the self-renewal of CSCs in human hepatoma cells [15]. Further studies demonstrated that SOX2 bound to the EnhII/Cp DNA and repressed the promoter activation through the high mobility group (HMG) domain, thereby suppressing HBV replication. We revealed that SOX2 repressed HBV replication in BALB/c mice and the HMG domain was required for SOX2-mediated repression of HBV replication in vivo These results revealed a distinct mechanism underlying SOX2 repressed HBV replication by binding to the viral EnhII/Cp and inhibiting the promoter activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
