Hepatitis B virus X protein counteracts high mobility group box 1 protein-mediated epigenetic silencing of covalently closed circular DNA

• DOI: 10.1371/journal.ppat.1010576
• Publication Date: 2022-06-09T17:25:56Z
• Authors: Elena S. Kim; Jun Zhou; Hu Zhang; Alexander Marchetti; Maarten van de Kl...; Dawei Cai; Xiaoyang Yu; Bidisha Mitra; Yuanjie Liu; Mu Wang; Ulrike Protzer; Haitao Guo
• Keywords: cccDNA; HBx; Minichromosome

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), serving as the viral persistence form and transcription template of HBV infection, hijacks host histone non-histone proteins to a minichromosome utilizes posttranslational modifications (PTMs) "histone code" for its transcriptional regulation. X protein (HBx) is known cccDNA activator. In this study we established dual system inducible reporter cell lines modelling infection with wildtype (wt) HBx-null HBV, both secreting HA-tagged HBeAg semi-quantitative marker transcription. The cccDNA-bound PTM profiling wt systems, using chromatin immunoprecipitation coupled quantitative PCR (ChIP-qPCR), confirmed that HBx essential maintenance at transcriptionally active state, characterized by markers. Differential proteomics analysis in revealed group-specific hits. One hits HBx-deficient condition was DNA-binding high mobility group box 1 (HMGB1). Its elevated association validated ChIP-qPCR assay stable systems vitro. Furthermore, experimental downregulation HMGB1 models resulted re-activation minichromosome, accompanied switch cccDNA-associated histones euchromatic state activating PTMs landscape subsequent upregulation Mechanistically, interacts prevents binding without affecting steady level HMGB1. Taken together, our results suggest novel restriction factor epigenetic silencing mechanism, which can be counteracted activator HBx.