Human Cytomegalovirus Infection Dysregulates the Canonical Wnt/β-catenin Signaling Pathway

Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in healthy individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. During infection, the virus exerts control over a multitude of host signaling pathways. Wnt/beta-catenin signaling, an essential pathway involved in cell cycle control, differentiation, embryonic development, placentation and metastasis, is frequently dysregulated by viruses. How HCMV infection affects this critical pathway is not currently known. In this study, we demonstrate that HCMV dysregulates Wnt/beta-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of beta-catenin and expression of beta-catenin target genes in these cells. HCMV infection leads to beta-catenin protein accumulation in a discrete juxtanuclear region. Levels of beta-catenin in membrane-associated and cytosolic pools, as well as nuclear beta-catenin, are reduced after infection; while transcription of the beta-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/beta-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function.