Borna Disease Virus Phosphoprotein Modulates Epigenetic Signaling in Neurons To Control Viral Replication

Abstract

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 plays 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 infected 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 it is 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 acetyltransferase 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 means to modulate viral replication and thus illustrate a fascinating example of virus-host cell interaction. IMPORTANCEPersistent 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 and 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 uncovered a novel modality of virus-cell interaction in which BDV phosphoprotein inhibits cellular histone acetylation by interfering with histone acetyltransferase activities. Manipulation of cellular histone acetylation is accompanied by a modulation of viral replication, revealing a perfect adaptation of this "ancient" virus to its host that may favor neuronal persistence and limit cellular damage.

Memory Impairment Induced by Borna Disease Virus 1 Infection is Associated with Reduced H3K9 Acetylation

“…Treatment with SAHA can enhance memory formation in rats and mice [17], and improves memory deficits in animal models of neurodegenerative disorders [18,19]. Infection with a laboratory BoDV-1 strain affects site-specific histone acetylation in cortical [20] and hippocampal neurons [21]. Moreover, our previous study showed that infection with a human BoDV-1 strain epigenetically impacts the human oligodendroglial (OL) cell proteome through histone acetylation [22].…”

MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2

“…Cortical primary neurons were prepared from Sprague-Dawley rat embryos at gestational day 17 as described previously (72). If needed, they were transfected using the Amaxa rat neuron nucleofector kit (Lonza) following the manufacturer instructions (5.10 6 neurons with 3 µg of plasmid DNA, by using the G-13 program on nucleofector apparatus) by plasmids expressing Flag-MeCP2 isoforms, kind gift from Angus Wilson (73).…”

Histone acetylation in neuronal (dys)function

“…At the molecular level, BDV has the remarkable property for a RNA virus to replicate into the nucleus, in close association with cellular chromatin (122). Moreover, a recent study from our team demonstrated that BDV infection resulted in a decrease of H2B and H4 acetylation on selected lysine residues in primary cultures of cortical neurons (123) (Figure 3). We also showed that the viral phosphoprotein, a cofactor of the viral polymerase, was responsible for this decrease in histone acetylation, by inhibiting cellular HAT activity.…”