The canonical Wnt/β-catenin signaling pathway stimulates herpes simplex virus 1 productive infection

Abstract

The ability of herpes simplex virus 1 (HSV-1) to replicate efficiently in differentiated cells is regulated by cellular factors that stimulate viral gene expression, cell survival, and viral morphogenesis. Activation of the canonical Wnt signaling pathway generally increases β-catenin protein levels, cell survival, and growth in dividing cells suggesting this important signaling pathway regulates productive infection. In this study, we demonstrated that a β-catenin specific small molecule inhibitor (iCRT14) reduced HSV-1 titers approximately 10-fold in primary human lung fibroblasts and Vero cells. Furthermore, β-catenin dependent transcription was increased at late times after infection and as expected iCRT14 reduced β-catenin dependent transcription. Although HSV-1 infection increased β-catenin steady state protein levels approximately 4-fold in Vero cells, there was only a nominal increase in human lung fibroblasts. We hypothesized that VP16 regulates β-catenin dependent transcription because VP16 is a viral regulatory protein expressed at late times after infection. In the absence of other viral proteins, VP16 increased β-catenin dependent transcription and β-catenin steady state protein levels. Collectively, these studies suggested the cellular transcription factor β-catenin stimulates productive infection, in part because VP16 enhances β-catenin dependent transcription.

HSV-1 single-cell analysis reveals the activation of anti-viral and developmental programs in distinct sub-populations

“…In accordance with its impact on late viral gene expression, β-catenin inhibition significantly reduced viral progeny formation (Figure 7F). This is in agreement with a recent report by Zhu and Jones (2018) showing iCRT14-reduced plaque formation in two other cell types (HLF and Vero). Similar results were obtained when β-catenin was silenced using siRNA (Figure 7G,H).…”

Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival

“…Numerous protein interactions and regulators of β-catenin have been characterized, with one known transcriptional co-activator being CBP for DNA binding. The association between this prosurvival factor and infection remains understudied as only a small number of studies exist linking HSV-1 or other viral infection to β-catenin activation (42)(43)(44). In this study, we show that multiple commercially available compounds targeting CREB and β-catenin systems demonstrate antiviral efficacy against HSV-1.…”

Comprehensive analysis of the host-virus interactome of SARS-CoV-2

“…These proteins are central components of the Wnt/beta-catenin signaling pathway. Previous studies revealed that activation of the Wnt/beta-catenin signaling pathway could stimulate viral replication 41,42 , and inhibition of this pathway could reduce the viral yield during productive viral infection 43,44 . Moreover, we showed that NSP10 interacts with several factors involved in the ERK1/ERK2 signaling pathway ( Figure 2 ), implying that SARS-CoV-2 may hijack the MAPK-ERK pathway to control the cell fate for the viral lifecycle, as reported for other viruses 45 .…”

“…These proteins are central components of the Wnt/beta-catenin signaling pathway. Previous studies revealed that activation of the Wnt/beta-catenin signaling pathway could stimulate viral replication 41,42 , and inhibition of this pathway could reduce the viral yield during productive viral infection 43,44 .…”