Sex-determining region Y box 4 (SOX4) suppresses Hepatitis B virus replication by inhibiting hepatocyte nuclear...

Area of Science:

• Virology
• Molecular Biology
• Hepatology

Background:

• Hepatitis B virus (HBV) infection is a global health crisis, leading to end-stage liver diseases like cirrhosis and hepatocellular carcinoma.
• Previous research suggested sex-determining region Y box 4 (SOX4) promotes HBV replication via a specific genomic motif, but this site is absent in most HBV strains.

Purpose of the Study:

• To investigate the actual role of SOX4 in HBV replication, particularly in strains lacking the previously identified binding site.
• To elucidate the molecular mechanism underlying SOX4's interaction with HBV replication.

Main Methods:

• Analysis of SOX4 binding to various HBV genotype strains.
• Experimental manipulation of endogenous SOX4 levels (knockdown).
• Assessment of HBV replication rates under different SOX4 conditions.
• Investigation of the role of hepatocyte nuclear factor 4α (HNF4α) in SOX4-mediated effects.

Main Results:

• The previously reported SOX4 binding motif (AACAAAG) was not found in the majority of HBV genotype strains.
• Contrary to prior findings, SOX4 was found to inhibit, not promote, the replication of most HBV strains.
• Knockdown of endogenous SOX4 significantly enhanced HBV replication.
• SOX4-induced suppression of HBV replication was primarily mediated by the inhibition of HNF4α expression.

Conclusions:

• SOX4 plays an inhibitory role in the replication of most HBV strains.
• This antiviral effect is mediated through the suppression of HNF4α expression.
• The findings challenge previous understandings and establish SOX4 as a key factor in controlling HBV replication in a broader range of strains.