hnRNPA2B1 induces HBV cccDNA degradation by recruiting APOBEC3B

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a persistent viral reservoir.
• The DNA damage response (DDR) influences cccDNA formation but its role in stability is unknown.

Purpose of the Study:

• To investigate the role of DDR factors in regulating HBV cccDNA stability.
• To identify novel host factors that restrict HBV replication.

Main Methods:

• Intersecting proteomic datasets of cccDNA-associated proteins with DDR factors.
• Identifying hnRNPA2B1 as a cccDNA-binding protein.
• Investigating hnRNPA2B1's mechanism of action, including interaction with G-quadruplex structures and APOBEC3B recruitment.
• Analyzing HBx-mediated degradation of hnRNPA2B1.

Main Results:

• hnRNPA2B1 acts as a restriction factor, binding cccDNA and promoting its degradation.
• hnRNPA2B1 interacts with cccDNA G-quadruplexes (G4-1, G4-7, G4-10).
• hnRNPA2B1 recruits APOBEC3B, inducing hypermutation and cccDNA decay.
• HBV protein HBx counteracts hnRNPA2B1 by inducing its polyubiquitination and proteasomal degradation.

Conclusions:

• A G-quadruplex-dependent surveillance pathway involving hnRNPA2B1 and APOBEC3B destabilizes cccDNA.
• HBx-induced hnRNPA2B1 ubiquitination is a viral evasion strategy maintaining cccDNA persistence.
• This virus-host interaction offers a potential therapeutic target for chronic HBV infection.