Human cytomegalovirus blocks canonical TGFβ signaling during lytic infection to limit induction of type I interferons.
Human cytomegalovirus blocks canonical TGFβ signaling during lytic infection to limit induction of type I interferons.
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DOI：
10.1371/journal.ppat.1009380
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发表时间：
2021-08
期刊：
影响因子：
6.7
通讯作者：
Hancock MH
中科院分区：
文献类型：
--
作者：
Pham AH;Mitchell J;Botto S;Pryke KM;DeFilippis VR;Hancock MH
人巨细胞病毒（HCMV）microRNAs（miRNAs）可显著改变宿主信号通路，以支持病毒生命周期并调节宿主细胞反应。在这里，我们表明，SMAD 3的表达是由HCMV miR-UL 22 A调节，并有助于IRF 7介导的诱导I型IFN和IFN刺激的基因（ISG）在人成纤维细胞。在野生型成纤维细胞中，外源TGFβ的加入以SMAD 3依赖性方式干扰miR-UL 22 A突变病毒的复制，但在缺乏IRF 7的细胞中不干扰，表明下调SMAD 3表达以限制IFN诱导对于有效的裂解复制是重要的。这些发现揭示了HCMV感染期间SMAD 3与先天免疫之间的新型相互作用，并强调了病毒miRNA在调节这些反应中的作用。细胞触发干扰素（IFN）反应以诱导限制病毒复制的细胞基因的表达。反过来，病毒已经进化出许多对策来避免IFN信号的影响。使用微小RNA（miRNA）突变病毒，我们已经发现了一种新的手段，调节干扰素的反应，在人巨细胞病毒（HCMV）感染。裂解性HCMV感染诱导TGFβ的产生，TGF β与TGFβ受体结合并激活受体相关的SMAD SMAD 3。SMAD 3与IRF 7一起诱导人成纤维细胞中IFNβ和下游IFN刺激基因的表达。为了抵消这一点，HCMV miR-UL 22 A与其他HCMV基因产物一起沿着直接靶向SMAD 3下调。用miR-UL 22 A突变病毒感染成纤维细胞会以SMAD 3和IRF 7依赖性方式增强I型IFN的产生，并且在存在TGFβ的情况下，病毒的生长会受到损害，但仅当SMAD 3和IRF 7都存在时，这凸显了TGFβ和先天免疫信号之间的独特相互作用。
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. Cells trigger the interferon (IFN) response to induce the expression of cellular genes that limit virus replication. In turn, viruses have evolved numerous countermeasures to avoid the effects of IFN signaling. Using a microRNA (miRNA) mutant virus we have uncovered a novel means of regulating the IFN response during human cytomegalovirus (HCMV) infection. Lytic HCMV infection induces the production of TGFβ, which binds to the TGFβ receptor and activates the receptor-associated SMAD SMAD3. SMAD3, together with IRF7, induces the expression of IFNβ and downstream IFN-stimulated genes in human fibroblasts. To counteract this, HCMV miR-UL22A, along with other HCMV gene products, directly targets SMAD3 for downregulation. Infection of fibroblasts with a miR-UL22A mutant virus results in enhanced type I IFN production in a SMAD3- and 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.
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