Human cytomegalovirus microRNAs target the Wnt signaling protein Dishevelled 3 to promote efficient reactivation in CD34 + hematopoietic progenitor cells
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Human cytomegalovirus (HCMV) establishes latency in CD34 + hematopoietic progenitor cells (HPCs), yet differentiation of these cells promotes viral gene expression and replication. HCMV must therefore precisely regulate the signaling networks that govern HPC fate to maintain latency while preserving the capacity for reactivation. Virally encoded microRNAs (miRNAs) represent powerful tools used by HCMV to manipulate cellular pathways that are involved in HPC fate decisions. Wnt (Wingless/Integrated)/β-catenin signaling represents one such pathway that plays a critical role in regulating both hematopoiesis and virus replication. Previous work determined that HCMV stimulates β-catenin activity during reactivation in CD34 + HPCs. In contrast, here we show that HCMV miRNAs miR-US5-2 and miR-US25-2 downregulate the Wnt pathway adaptor protein Dvl3 during latency and that this downregulation is required for subsequent virus reactivation. These findings support a model of temporally distinct regulation of Wnt pathway components during latency and reactivation.
IMPORTANCE
Human cytomegalovirus (HCMV) persists for life by establishing latency in hematopoietic progenitor cells followed by periodic reactivation events. How the virus controls host signaling pathways to influence these events remains incompletely understood. Here, we show that HCMV-encoded microRNAs (miRNAs) downregulate the Wnt signaling adaptor Dvl3 during latency, contrasting with the activation of the Wnt/β-catenin signaling that occurs during reactivation. These findings reveal that HCMV does not uniformly activate or inhibit Wnt signaling but instead regulates this pathway in opposing directions at different stages of infection. This temporal regulation of Wnt signaling highlights how HCMV coordinates viral infection with changes in progenitor cell state and identifies viral miRNAs as important regulators of the balance between latency and reactivation.
