Abstract
Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGFβ interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.
Highlights
Human Cytomegalovirus (HCMV) has co-evolved with its host over millions of years, resulting in exquisite control of both the cellular environment and the viral lifecycle that is highly cell type-dependent
Lytic HCMV infection induces the production of TGFβ, which binds to the TGFβ receptor and activates the receptor-associated SMAD SMAD3
Infection of fibroblasts with a miR-UL22A mutant virus results in enhanced type I IFN production in a SMAD3- and interferon regulatory factor 7 (IRF7)-dependent manner and the virus is impaired for growth in the presence of TGFβ, but only when both SMAD3 and IRF7 are present, highlighting the unique interaction between TGFβ and innate immune signaling
Summary
Human Cytomegalovirus (HCMV) has co-evolved with its host over millions of years, resulting in exquisite control of both the cellular environment and the viral lifecycle that is highly cell type-dependent. The specific transcriptional outcomes of TGFβ signaling depends on cell type, TGFβ concentration and presence of additional signaling regulators resulting in either transcriptional activation or repression of different subsets of cellular genes (reviewed in [11,12]). In addition to the choice of DNA binding partners, the recruitment of transcriptional coactivators, such as CBP/p300 [16] or corepressors, such as TGIF [17], SKI or SnoN [18] is critical for determining the outcome of TGFβ signaling. The transcriptional outcome of canonical TGFβ signaling critically depends on the presence of a SMAD DNA binding cofactor as well as coactivators or corepressors, whose expression and localization are regulated by additional cellular signaling pathways in a context-dependent and cell type-specific manner [12]
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