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

Abstract

Bovine herpesvirus type 1 (BoHV-1) is a significant cofactor for bovine respiratory disease complex (BRDC), the most important inflammatory disease in cattle. BoHV-1 infection in cell cultures induces overproduction of pathogenic reactive oxygen species (ROS) and the depletion of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a master transcriptional factor regulating a panel of antioxidant and cellular defense genes in response to oxidative stress. In this study, we reported that the virus productive infection in MDBK cells at the later stage significantly decreased the expression levels of heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1) proteins, the canonical downstream targets regulated by Nrf2, inhibited Nrf2 acetylation, reduced the accumulation of Nrf2 proteins in the nucleus, and relocalized nuclear Nrf2 proteins to form dot-like staining patterns in confocal microscope assay. The differential expression of Kelch-like ECH associated protein 1 (KEAP1) and DJ-1 proteins as well as the decreased association between KEAP1 and DJ-1 promoted Nrf2 degradation through the ubiquitin proteasome pathway. These data indicated that the BoHV-1 infection may significantly suppress the Nrf2 signaling pathway. Moreover, we found that there was an association between Nrf2 and LaminA/C, H3K9ac, and H3K18ac, and the binding ratios were altered following the virus infection. Taken together, for the first time, we provided evidence showing that BoHV-1 infection inhibited the Nrf2 signaling pathway by complicated mechanisms including promoting Nrf2 degradation, relocalization of nuclear Nrf2, and inhibition of Nrf2 acetylation.

Arsenite Inhibits Tissue-Type Plasminogen Activator Synthesis through NRF2 Activation in Cultured Human Vascular Endothelial EA.hy926 Cells

“…To confirm that Trolox inhibits the activation of the NRF2 pathway induced by arsenite, we examined the effect of Trolox on arsenite-induced intranuclear NRF2 protein levels. As shown in Figure 6 d, Trolox alone increased the NRF2 protein level, as previously reported [ 38 , 39 ], although it did not change the t-PA mRNA expression ( Figure 5 b). When we calculated the ratio of NRF2/Lamin A in the arsenite-treated groups to that in the corresponding control groups, and we found that the arsenite-induced increase in the NRF2 protein ratio was decreased by 1-mM Trolox treatment ( Figure 6 e).…”

Upregulation of nuclear factor E2-related factor 2 (Nrf2) represses the replication of herpes simplex virus type 1

“…It has been reported that Nrf2 degradation caused by viral infection is regulated by Keap1-dependent or Keap1-independent ubiquitin–proteasome pathways [ 19 ]. Bovine herpesvirus type infection stimulates Nrf2 degradation through the Keap1-dependent ubiquitin proteasome pathway [ 20 ]. However, Dengue virus uses the NS2B3 protease complex to strategically target Nrf2 for degradation [ 18 ].…”

Bovine Airway Models: Approaches for Investigating Bovine Respiratory Disease

“…Like other Herpes viruses, BHV-1 maintains its presence throughout the host’s lifespan and can be passed onto calves . Downstream effects of infection include upregulation of genes involved in responding to reactive oxygen species (ROS) . BHV-1 is also known to cause reproductive tract disease in infected cattle, resulting in infertility, miscarriages, and stillbirths. , Clinical signs of BHV-1 include a high fever, inflamed nares, and excessive nasal discharge …”