DNA Sensor ABCF1 Phase Separates With cccDNA to Inhibit Hepatitis B Virus Replication.

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is crucial for viral persistence.
• The host innate immune response to cccDNA remains incompletely understood.

Purpose of the Study:

• To identify host factors that interact with cccDNA and restrict HBV replication.
• To elucidate the mechanism by which the host innate immune system combats cccDNA.

Main Methods:

• cccDNA-hepatic protein interaction profiling.
• Identification and characterization of ATP-binding cassette subfamily F member 1 (ABCF1) as a cccDNA-binding protein.
• Analysis of phase separation, interferon pathway activation, and HBV transcription inhibition.

Main Results:

• ABCF1 was identified as a novel cccDNA-binding protein and a host restriction factor for HBV.
• ABCF1 recognizes cccDNA and forms phase-separated condensates, activating type I/III interferon (IFN-I/III) signaling.
• ABCF1 inhibits HBV transcription by preventing Pol II accumulation on cccDNA.
• HBV counteracts this by reducing ABCF1 expression via HBx-mediated degradation of SOX4.

Conclusions:

• ABCF1-cccDNA phase separation provides a dual mechanism for host defense against HBV by activating innate immunity and inhibiting viral transcription.
• This study reveals a novel host-pathogen interaction and offers a potential therapeutic target for HBV infection.