The induction of Smad signalling by the extracellular ligand TGF‐β promotes tissue plasticity and cell migration in developmental and pathological contexts. Here, we show that vaccinia virus (VACV) stimulates the activity of Smad transcription factors and expression of TGF‐β/Smad‐responsive genes at the transcript and protein levels. Accordingly, infected cells share characteristics to those undergoing TGF‐β/Smad‐mediated epithelial‐to‐mesenchymal transition (EMT). Depletion of the Smad4 protein, a common mediator of TGF‐β signalling, results in an attenuation of viral cell‐to‐cell spread and reduced motility of infected cells. VACV induction of TGF‐β/Smad‐responsive gene expression does not require the TGF‐β ligand or type I and type II TGF‐β receptors, suggesting a novel, non‐canonical Smad signalling pathway. Additionally, the spread of ectromelia virus, a related orthopoxvirus that does not activate a TGF‐β/Smad response, is enhanced by the addition of exogenous TGF‐β. Together, our results indicate that VACV orchestrates a TGF‐β‐like response via a unique activation mechanism to enhance cell migration and promote virus spread.

中文翻译：

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痘苗病毒的细胞间传播由不依赖 TGF-β 的 Smad4 信号传导促进。

细胞外配体 TGF-β 对 Smad 信号的诱导促进了发育和病理环境中的组织可塑性和细胞迁移。在这里，我们表明痘苗病毒 (VACV) 在转录物和蛋白质水平上刺激 Smad 转录因子的活性和 TGF-β/Smad 反应基因的表达。因此，受感染的细胞与那些经历 TGF-β/Smad 介导的上皮间质转化 (EMT) 的细胞具有相同的特征。Smad4 蛋白（TGF-β 信号传导的常见介质）的消耗导致病毒细胞间传播减弱和受感染细胞运动性降低。VACV 诱导 TGF-β/Smad 响应基因表达不需要 TGF-β 配体或 I 型和 II 型 TGF-β 受体，这表明存在一种新的、非经典的 Smad 信号通路。此外，添加外源性 TGF-β 可增强 ectromelia 病毒（一种不激活 TGF-β/Smad 反应的相关正痘病毒）的传播。总之，我们的结果表明 VACV 通过独特的激活机制协调 TGF-β 样反应，以增强细胞迁移并促进病毒传播。