Hepatitis Delta Virus histone mimicry drives the recruitment of chromatin remodelers for viral RNA replication

Natali Abeywickrama-Samarakoon, Jean-Claude Cortay, Camille Sureau, Susanne Müller, Dulce Alfaiate, Francesca Guerrieri, Apirat Chaikuad, Martin Schröder, Philippe Merle, Massimo Levrero () and Paul Dény ()
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Natali Abeywickrama-Samarakoon: INSERM, U1052 UMR CNRS 5286, Cancer Research Center of Lyon (CRCL)
Jean-Claude Cortay: INSERM, U1052 UMR CNRS 5286, Cancer Research Center of Lyon (CRCL)
Camille Sureau: Laboratoire de Virologie Moléculaire, INSERM U1134, Institut National de la Transfusion Sanguine
Susanne Müller: Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University
Dulce Alfaiate: INSERM, U1052 UMR CNRS 5286, Cancer Research Center of Lyon (CRCL)
Francesca Guerrieri: INSERM, U1052 UMR CNRS 5286, Cancer Research Center of Lyon (CRCL)
Apirat Chaikuad: Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University
Martin Schröder: Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University
Philippe Merle: INSERM, U1052 UMR CNRS 5286, Cancer Research Center of Lyon (CRCL)
Massimo Levrero: INSERM, U1052 UMR CNRS 5286, Cancer Research Center of Lyon (CRCL)
Paul Dény: INSERM, U1052 UMR CNRS 5286, Cancer Research Center of Lyon (CRCL)

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. HDV RNA genome synthesis is carried out in infected cells by cellular RNA polymerases with the assistance of the small hepatitis delta antigen (S-HDAg). Here we show that S-HDAg binds the bromodomain (BRD) adjacent to zinc finger domain 2B (BAZ2B) protein, a regulatory subunit of BAZ2B-associated remodeling factor (BRF) ISWI chromatin remodeling complexes. shRNA-mediated silencing of BAZ2B or its inactivation with the BAZ2B BRD inhibitor GSK2801 impairs HDV replication in HDV-infected human hepatocytes. S-HDAg contains a short linear interacting motif (SLiM) KacXXR, similar to the one recognized by BAZ2B BRD in histone H3. We found that the integrity of the S-HDAg SLiM sequence is required for S-HDAg interaction with BAZ2B BRD and for HDV RNA replication. Our results suggest that S-HDAg uses a histone mimicry strategy to co-activate the RNA polymerase II-dependent synthesis of HDV RNA and sustain HDV replication.

Date: 2020
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DOI: 10.1038/s41467-020-14299-9

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