Borna disease virus phosphoprotein modulates epigenetic signaling in neurons to control viral replication.

Understanding the modalities
of interaction of neurotropic viruses with their target cells represents
a major challenge that may improve our knowledge of many human
neurological disorders for which viral origin is suspected. Borna
disease virus (BDV) represents an ideal model to analyze the molecular
mechanisms of viral persistence in neurons and its consequences for
neuronal homeostasis. It is now established that BDV ensures its
long-term maintenance in infected cells through a stable interaction of
viral components with the host cell chromatin, in particular with core
histones. This has led to our hypothesis that such an interaction may
trigger epigenetic changes in the host cell. Here, we focused on histone
acetylation, which play key roles in epigenetic regulation of gene
expression, notably for neurons. We performed a comparative analysis of
histone acetylation patterns of neurons infected or not by BDV, which
revealed that infection decreases histone acetylation on selected lysine
residues. We showed that the BDV phosphoprotein (P) is responsible for
these perturbations, even when expressed alone independently of the
viral context, and that this action depends on its phosphorylation by
protein kinase C. We also demonstrated that BDV P inhibits cellular
histone acetyl transferase activities. Finally, by pharmacologically
manipulating cellular acetylation levels, we observed that inhibiting
cellular acetyl transferases reduces viral replication in cell culture.
Our findings reveal that manipulation of cellular epigenetics by BDV
could be a mean to modulate viral replication and thus illustrate a
fascinating example of virus/host cell interaction.


DNA viruses often subvert the mechanisms that regulate cellular
chromatin dynamics, thereby benefitting from the resulting epigenetic
changes to create a favorable milieu for their latent/persistent states.
Here, we reasoned that Borna Disease Virus (BDV), the only RNA virus
known to durably persist in the nucleus of infected cells, notably
neurons, might employ a similar mechanism. In this study, we uncover a
novel modality of virus/cell interaction in which BDV phosphoprotein
inhibits cellular histone acetylation by interfering with histone acetyl
transferase activities. Manipulation of cellular histone acetylation is
accompanied by a modulation of viral replication, revealing the perfect
adaptation of this "ancient" virus to its host that may favor neuronal
persistence and limit cellular damage.

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