Abstract
The histone H3.3 chaperone DAXX is implicated in formation of heterochromatin and transcription silencing, especially for newly infecting DNA virus genomes entering the nucleus. Epstein-Barr virus (EBV) can efficiently establish stable latent infection as a chromatinized episome in the nucleus of infected cells. The EBV tegument BNRF1 is a DAXX-interacting protein required for the establishment of selective viral gene expression during latency. Here we report the structure of BNRF1 DAXX-interaction domain (DID) in complex with DAXX histone-binding domain (HBD) and histones H3.3-H4. BNRF1 DID contacts DAXX HBD and histones through non-conserved loops. The BNRF1-DAXX interface is responsible for BNRF1 localization to PML-nuclear bodies typically associated with host-antiviral resistance and transcriptional repression. Paradoxically, the interface is also required for selective transcription activation of viral latent cycle genes required for driving B-cell proliferation. These findings reveal molecular details of virus reprogramming of an antiviral histone chaperone to promote viral latency and cellular immortalization.
Highlights
The histone H3.3 chaperone DAXX is implicated in formation of heterochromatin and transcription silencing, especially for newly infecting DNA virus genomes entering the nucleus
We further show that the BNRF1-DAXX interface is responsible for BNRF1 localization to PML-nuclear bodies that are involved in host-antiviral resistance and transcriptional repression, and is required for the selective transcription activation of viral latent cycle genes required for driving B-cell proliferation
On the basis of earlier findings by our groups and others revealing the structure of the ternary complex of the histone-binding domain (HBD) of chaperone DAXX bound to the histone H3.3-H4 dimer[21,22], and biochemical evidence for quaternary complex formation between this ternary complex and the DAXX-interaction domain (DID) of BNRF1, we had successfully reconstituted and crystallized the quaternary complex of the BNRF1 DID with the chaperone DAXX HBD and H3.3-H4 dimer
Summary
The histone H3.3 chaperone DAXX is implicated in formation of heterochromatin and transcription silencing, especially for newly infecting DNA virus genomes entering the nucleus. The interface is required for selective transcription activation of viral latent cycle genes required for driving B-cell proliferation These findings reveal molecular details of virus reprogramming of an antiviral histone chaperone to promote viral latency and cellular immortalization. We further show that the BNRF1-DAXX interface is responsible for BNRF1 localization to PML-nuclear bodies that are involved in host-antiviral resistance and transcriptional repression, and is required for the selective transcription activation of viral latent cycle genes required for driving B-cell proliferation. These data reveal how the virus protein BNRF1 hijacks the cellular antiviral histone chaperone DAXX to promote viral latency and cellular immortalization
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