RNA Helicase DDX5 in Association With IFI16 and the Polycomb Repressive Complex 2 Silences Transcription of the Hepatitis B Virus by Interferon

• DOI: 10.1002/jmv.70118
• Publication Date: 2024-12-16T12:18:54Z
• Authors: Zhili Li; Naimur Rahman; Cheng Bi; Rodrigo Mohallem; Aryamav Pattnaik; Majid Kazemian; Fang Huang; Uma K. Aryal; Ourania Andrisani
• Keywords: PRC2; Transcription; cccDNA; Ectopic expression

ABSTRACT RNA helicase DDX5 is a host restriction factor for hepatitis B virus (HBV) biosynthesis. Mass spectrometry (LC‐MS/MS) identified significant DDX5‐interacting partners, including interferon‐inducible protein 16 (IFI16) and RBBP4/7, an auxiliary subunit of polycomb repressive complex 2 (PRC2). co‐eluted with IFI16, core PRC2 subunits in size exclusion chromatography fractions derived from native nuclear extracts. Native gel electrophoresis immunoprecipitants revealed 750 kDa DDX5/IFI16/PRC2 complex, validated by nanoscale co‐localization via super‐resolution microscopy. Prior studies demonstrated that IFI16 suppresses HBV transcription binding to the interferon‐sensitive response element covalently closed circular DNA (cccDNA), reducing H3 acetylation increasing H3K27me3 levels unknown mechanism. Herein, we demonstrate ectopic expression inhibited recombinant rcccDNA, correlating increased reduced acetylation, elevated H3K27me3, determined chromatin immunoprecipitation. Importantly, inhibitory effect on was reversed siRNA‐mediated knockdown EZH2, methyltransferase PRC2. This reversal associated decreased enhanced H3K27me3. Similarly, endogenous induced interferon‐α rcccDNA DDX5‐ PRC2‐dependent manner. In HBV‐infected HepG2‐NTCP cells, antiviral abrogated upon underscoring crucial role IFI16‐mediated response. conclusion, interferon, partners bind cccDNA, directing epigenetically silence cccDNA chromatin, thereby regulating immune signaling transcription.