Viral reprogramming of the Daxx histone H3.3 chaperone during early Epstein-Barr virus infection

Tsai, K., Chan, L., Gibeault, R., Conn, K., Dheekollu, J., Domsic, J., Marmorstein, R., Schang, L. M. and Lieberman, P. M. (2014) Viral reprogramming of the Daxx histone H3.3 chaperone during early Epstein-Barr virus infection. Journal of Virology, 88(24), pp. 14350-14363. (doi: 10.1128/JVI.01895-14) (PMID:25275136) (PMCID:PMC4249116)

Abstract

Host chromatin assembly can function as a barrier to viral infection. Epstein-Barr virus (EBV) establishes latent infection as chromatin-assembled episomes in which all but a few viral genes are transcriptionally silent. The factors that control chromatin assembly and guide transcription regulation during the establishment of latency are not well understood. Here, we demonstrate that the EBV tegument protein BNRF1 binds the histone H3.3 chaperone Daxx to modulate histone mobility and chromatin assembly on the EBV genome during the early stages of primary infection. We demonstrate that BNRF1 substitutes for the repressive cochaperone ATRX to form a ternary complex of BNRF1-Daxx-H3.3-H4, using coimmunoprecipitation and size-exclusion chromatography with highly purified components. FRAP (fluorescence recovery after photobleaching) assays were used to demonstrate that BNRF1 promotes global mobilization of cellular histone H3.3. Mutation of putative nucleotide binding motifs on BNRF1 attenuates the displacement of ATRX from Daxx. We also show by immunofluorescence combined with fluorescence in situ hybridization that BNRF1 is important for the dissociation of ATRX and Daxx from nuclear bodies during de novo infection of primary B lymphocytes. Virion-delivered BNRF1 suppresses Daxx-ATRX-mediated H3.3 loading on viral chromatin as measured by chromatin immunoprecipitation assays and enhances viral gene expression during early infection. We propose that EBV tegument protein BNRF1 replaces ATRX to reprogram Daxx-mediated H3.3 loading, in turn generating chromatin suitable for latent gene expression.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Conn, Dr Kristen
• Authors: Tsai, K., Chan, L., Gibeault, R., Conn, K., Dheekollu, J., Domsic, J., Marmorstein, R., Schang, L. M., and Lieberman, P. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Journal of Virology
• Journal Abbr.: J. Virol.
• Publisher: American Society for Microbiology
• ISSN: 0022-538X
• ISSN (Online): 1098-5514