The Involvement of Histone H3 Acetylation in Bovine Herpesvirus 1 Replication in MDBK Cells

Abstract

During bovine herpesvirus 1 (BoHV-1) productive infection in cell cultures, partial of intranuclear viral DNA is present in nucleosomes, and viral protein VP22 associates with histones and decreases histone H4 acetylation, indicating the involvement of histone H4 acetylation in virus replication. In this study, we demonstrated that BoHV-1 infection at the late stage (at 24 h after infection) dramatically decreased histone H3 acetylation [at residues K9 (H3K9ac) and K18 (H3K18ac)], which was supported by the pronounced depletion of histone acetyltransferases (HATs) including CBP/P300 (CREB binding protein and p300), GCN5L2 (general control of amino acid synthesis yeast homolog like 2) and PCAF (P300/CBP-associated factor). The depletion of GCN5L2 promoted by virus infection was partially mediated by ubiquitin-proteasome pathway. Interestingly, the viral replication was enhanced by HAT (histone acetyltransferase) activator CTPB [N-(4-Chloro-3-trifluoromethylphenyl)-2-ethoxy-6-pentadecylbenzamide], and vice versa, inhibited by HAT inhibitor Anacardic acid (AA), suggesting that BoHV-1 may take advantage of histone acetylation for efficient replication. Taken together, we proposed that the HAT-dependent histone H3 acetylation plays an important role in BoHV-1 replication in MDBK (Madin-Darby bovine kidney) cells.

Bovine Herpesvirus 1 Productive Infection Led to Inactivation of Nrf2 Signaling through Diverse Approaches

“…Based on these results, we assumed that if the ratio between Nrf2 and H3K9ac/H3K18ac was arbitrarily set as 1 (Nrf2 : H3K9ac/H3K18ac = 1) in the control, the ratio would be less than 1 (Nrf2 : H3K9ac/H3K18ac < 1) in the virus-infected cells, suggesting that the virus infection reduced the association ratio between Nrf2 and H3K9ac/H3K18ac. Since we have previously reported that the virus infection significantly reduced the protein levels of both H3K9ac and H3K18ac [37], the association between Nrf2 and H3K9ac/H3K18ac supported our findings that virus infection relocalized nuclear Nrf2. It is highly possible that more Nrf2 protein was relocalized to the transcriptionally active chromatin in the virus-infected cells, which is a possible mechanism to overcome adverse effects of Nrf2 depletion during virus infection.…”

“…It has been reported that the degradation of Nrf2 protein through the ubiquitin proteasome pathway is regulated by either KEAP1-dependent or KEAP1-independent mechanisms [36]. To confirm that the ubiquitin proteasome pathway was involved in Nrf2 degradation in the virus-infected MDBK cells, the cells were exposed to proteasome inhibitor MG132 throughout viral infection as described previously [37]. We have reported that MG132 at a concentration of 1 μ M had no cytotoxicity to MDBK cells [37].…”

“…To confirm that the ubiquitin proteasome pathway was involved in Nrf2 degradation in the virus-infected MDBK cells, the cells were exposed to proteasome inhibitor MG132 throughout viral infection as described previously [37]. We have reported that MG132 at a concentration of 1 μ M had no cytotoxicity to MDBK cells [37]. The treatment of MG132 (1 μ M) partially restored the Nrf2 depletion induced by the virus infection, and its protein level was increased to ~3.5-fold relative to the mock-treated infected control (Figures 3(a) and 3(b)), indicating that the ubiquitin proteasome pathway was potentially involved in the Nrf2 depletion in virus-infected cells.…”

“…Since H3K9ac and H3K18ac are markers of transcriptional active chromatin, it is highly possible that Nrf2 preferentially binds to transcriptional active chromatin to overcome the adverse effects of Nrf2 depletion following virus infection. In addition, the virus infection reduced the association ratio between Nrf2 and H3K9ac/H3K18ac (Figure 8) and decreased the protein levels of both H3K9ac and H3K18ac [37], which potentially induce nuclear Nrf2 relocalization. This is an interesting finding which needs further study to reveal the biological effects of these associations.…”

Quantitative Analysis of Lysine Acetylation in Vero Cells Infected With Peste Des Petits Ruminants Virus

“…Increasing evidence indicates that histone acetylation modification has an important role in virus infection. Several previous studies have reported virus induced changes in histone lysine acetylation sites, such as adenovirus [78], borna disease virus [31,79], Influenza virus [30,80], HIV [81], Zaire Ebolavirus [82], bovine herpesvirus [83], parvovirus [84]. In this study, nine histone lysine acetylation sites were significantly regulated, of which eight sites were down-regulated.…”