Proteomic Analysis Reveals Selective Impediment of Neuronal Remodeling upon Borna Disease Virus Infection

Suberbielle, Elsa; Stella, Alexandre; Pont, Frédéric; Monnet, Céline; Mouton, Emmanuelle; Lamouroux, Lucile; Monsarrat, Bernard; Gonzalez–Dunia, Daniel

doi:10.1128/jvi.01615-08

Cited by 31 publications

(42 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed that BDV infection led to a significant decrease of H2B acetylation on K5 and K20 (33% and 26% decreases, respectively) ( Fig. 1A), consistent with our previous proteomics findings (9). In addition, infection also induced a decrease of acetylation on K15 but not on K12.…”

Section: Resultssupporting

confidence: 80%

“…Based on these findings, it was tempting to hypothesize that BDV may modify the host cell chromatin or interact with factors controlling chromatin dynamics. Moreover, in a previous proteomic analysis performed using primary neuronal culture protein extracts, we observed that acetylation of histone H2B was changed upon infection, suggesting that epigenetic signaling could indeed be affected by BDV (9).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Bonnaud

Szelechowski

Bétourné

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 80%

mentioning

confidence: 99%

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

Bonnaud

Szelechowski

Bétourné

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, it was revealed that MeCP2 is expressed not only in neurons but also in astrocytes and that MeCP2 deficiency in astrocytes causes several abnormalities, such as in BDNF regulation, cytokine production, and neuronal dendritic induction (13). Interestingly, a recent report using proteomic analysis revealed that BDV infection decreases the expression level of MeCP2 in neuronal cells (27). Although it is tempting to speculate that BDV P influences the function of MeCP2 through interference with its phosphorylation, since the function of MeCP2 appears to be regulated by phosphorylation in the CNS (9,32), the expression levels of IGFBP3 are not significantly different in C6 cells transfected with wild-type P and those infected with a phosphorylation mutant of P, P S26/28A (31; data not shown).…”

Section: Borna Disease Virus (Bdv) Is a Highly Neurotropic Negativestmentioning

confidence: 99%

Upregulation of Insulin-Like Growth Factor Binding Protein 3 in Astrocytes of Transgenic Mice That Express Borna Disease Virus Phosphoprotein

Honda

Fujino

Okuzaki

et al. 2011

J Virol

View full text Add to dashboard Cite

In a previous study, we demonstrated that transgenic mice that express Borna disease virus (BDV) phosphoprotein (P) in astrocytes show striking neurobehavioral abnormalities resembling those in BDV-infected animals. To understand the molecular disturbances induced by the expression of P in astrocytes, we performed microarray analysis with cultured astroglial cells transiently expressing P. We showed that expression of insulin-like growth factor binding protein 3 mRNA increases not only in P-expressing cultured cells but also in astrocytes from the cerebella of P transgenic mice (P-Tg). Furthermore, we demonstrated that insulin-like growth factor signaling is disturbed in the P-Tg cerebellum, a factor that might be involved in the increased vulnerability of Purkinje cell neurons in the brain.Borna disease virus (BDV) is a highly neurotropic negativestranded RNA virus that belongs to the order Mononegavirales. Many studies have demonstrated that natural infections with BDV occur worldwide in a variety of vertebrate species, suggesting that the host range of the virus includes all warmblooded animals (12). BDV persistently infects the central nervous systems (CNSs) of many animal species and causes neurobehavioral disorders such as anxiety, aggression, hyperactivity, abnormal play behavior, and cognitive deficits (6,20). Previous studies have demonstrated that BDV infection in the rat model induces autism-like neurodevelopmental and behavioral disturbances without the characteristic inflammatory responses in the brain (6,12,19). Therefore, studies of this virus infection in animals could provide a valuable model to investigate the neuropathology of behavioral and neurodevelopmental disorders (1,18,19).In a previous study, we reported the generation of transgenic mice expressing BDV phosphoprotein (P) selectively in astrocytes (8). These transgenic mice (P-Tg) showed striking neurobehavioral abnormalities that resemble those described for BDV-infected animals, such as enhanced intermale aggressiveness, hyperactivity, and spatial reference memory deficit (8). Furthermore, P-Tg exhibited abnormalities in the expression of neurotropic factors and neurotransmitters, as well as in synaptic density. The study provided a novel approach to understanding not only the link between viral infection and neurobehavioral disorders but also the relationship between neurobehavioral disorders and astrocyte dysfunctions (26,29).In an effort to understand the molecular disturbances of glial cells triggered by the expression of BDV P, we performed microarray analysis with C6 rat glioma cells expressing either green fluorescent protein (GFP) (C6-GFP cells) or BDV P (C6-P cells), using Agilent's whole rat genome DNA array, in which 41,090 different cDNA probes are spotted on glass slides. cDNA was generated from both cell lines at 1 week postelectroporation and hybridized to microarrays. Affected genes in BDV P-expressing C6 rat glioma cells were extracted using GeneSpring software (P-value cutoff of Ͻ0.01), and we found that the expressi...

show abstract

“…The BDV Hu-H1 strain is one of the first three human strains derived from mentally affected patients (12). These strains have been partially characterized by sequencing (13). The remaining neurons were maintained as a control sample.…”

Section: Primary Culture Of Hippocampal Neurons and Viral Infectionmentioning

confidence: 99%

Identification of suitable reference genes for BDV-infected primary rat hippocampal neurons

Mao

Zhang

Guo

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Borna disease virus (BDV) is a neurotropic RNA virus that infects the limbic system of mammals and results in behavioral disorders. The hippocampus is a core region in the limbic system, which contributes to memory and learning and is important in the regulation of emotion. However, no validated microRNA housekeeping genes have yet been identified in BDV-infected rat primary hippocampal neurons. Proper normalization is key in accurate miRNA expression analysis. The present study used reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to evaluate the expression stability of 10 commonly used reference genes 5S, U6, E2 small nucleolar RNA (snoRNA), in BDV-infected rat hippocampal neurons and non-infected controls across 12 days post-infection. The data was analyzed by four statistical algorithms: geNorm, NormFinder, BestKeeper, and the comparative Δ-Ct method. Subsequently, the most suitable reference genes (miR-101a and U87) and the least suitable (snoRNA) were determined by the RankAggreg package. miR-155 was selected as a standard by which to evaluate the most and least suitable reference genes. When normalized to the most stable reference gene there were significant differences between the two groups. However, when the data were normalized to the less stably expressed gene, the results were not significant. miR-101a was recommended as a suitable reference gene for BDV-infected rat primary hippocampal neurons.

show abstract

Proteomic Analysis Reveals Selective Impediment of Neuronal Remodeling upon Borna Disease Virus Infection

Cited by 31 publications

References 58 publications

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

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

Upregulation of Insulin-Like Growth Factor Binding Protein 3 in Astrocytes of Transgenic Mice That Express Borna Disease Virus Phosphoprotein

Identification of suitable reference genes for BDV-infected primary rat hippocampal neurons

Contact Info

Product

Resources

About