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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 TGF\u03b2 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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009380","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T15:04:39Z","timestamp":1629385479000},"page":"e1009380","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Human cytomegalovirus blocks canonical TGF\u03b2 signaling during lytic infection to limit induction of type I interferons"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-4826","authenticated-orcid":true,"given":"Andrew H.","family":"Pham","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0323-2662","authenticated-orcid":true,"given":"Jennifer","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Botto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kara M.","family":"Pryke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor R.","family":"DeFilippis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2945-0147","authenticated-orcid":true,"given":"Meaghan H.","family":"Hancock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"ppat.1009380.ref001","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.3389\/fimmu.2019.02751","article-title":"Interferon-Independent Innate Responses to Cytomegalovirus","volume":"10","author":"CL Ashley","year":"2019","journal-title":"Front Immunol"},{"issue":"9","key":"ppat.1009380.ref002","doi-asserted-by":"crossref","DOI":"10.3390\/v10090447","article-title":"Who\u2019s Driving? 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