Human Herpesvirus 6A Replication via Beta Interferon Induction.
Human Herpesvirus 6A Replication via Beta Interferon Induction.
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通过 Beta 干扰素诱导进行人类疱疹病毒 6A 复制。
DOI：
10.1128/jvi.01264-22
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Mori Y.
中科院分区：
文献类型：
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作者：
1.Aktar S;Arii J;Nguyen TTH;Huang JR;Nishimura M;Mori Y.
刺激诱导的 cAMP 反应元件 (CRE) 结合蛋白 (CREB) 转录因子家族与 CRE 结合，调节多种细胞反应，包括增殖、存活和分化。人类疱疹病毒 6A (HHV-6A) 属于 Betaherpesvirinae 亚科，是一种嗜淋巴细胞疱疹病毒，常见于神经炎症性疾病患者。之前的报道暗示了 CRE 在 HHV-6A 生命周期中的重要性，尽管转录因子与 CRE 结合对病毒复制的影响尚未完全阐明。在这项研究中，我们分析了 CREB 转录因子家族在 HHV-6A 复制过程中的作用。我们发现 HHV-6A 感染增强了 CREB 家族成员 CREB1 和激活转录因子 1 (ATF1) 的磷酸化。 CREB1 或 ATF1 的敲除 (KO) 增强了病毒基因表达和病毒复制。 ATF1-KO细胞上清液中病毒产量的增加大于CREB1-KO细胞上清液中的病毒产量。转录组测序 (RNA-seq) 分析显示，ATF1-KO 细胞中先天免疫系统的传感器下调，并且感染 HHV-6A 的这些细胞中 β 干扰素 (IFN-β) 和 IFN 调节基因的 mRNA 减少。 ATF1-KO细胞的IFN-β处理显着降低了子代病毒产量，表明病毒复制的增强是由IFN-β的减少引起的。综上所述，我们的结果表明，ATF1 在 HHV-6A 感染期间被激活，并通过 IFN-β 诱导来限制病毒复制。 重要性 人类疱疹病毒 6A (HHV-6A) 是一种与阿尔茨海默病有关的普遍存在的疱疹病毒，尽管其在发病机制中的作用尚未得到证实。在这里，我们发现转录因子 ATF1 通过 IFN-β 诱导来限制 HHV-6A 复制。我们的研究为 ATF1 在先天病毒免疫中的作用提供了新的见解，并揭示了 IFN-β 对于调节 HHV-6A 复制的重要性，这可能会损害 HHV-6A 发病机制。
The stimulus-induced cAMP response element (CRE)-binding protein (CREB) family of transcription factors bind to CREs to regulate diverse cellular responses, including proliferation, survival, and differentiation. Human herpesvirus 6A (HHV-6A), which belongs to theBetaherpesvirinaesubfamily, is a lymphotropic herpesvirus frequently found in patients with neuroinflammatory diseases. Previous reports implicated the importance of CREs in the HHV-6A life cycle, although the effects of the binding of transcription factors to CREs in viral replication have not been fully elucidated. In this study, we analyzed the role of the CREB family of transcription factors during HHV-6A replication. We found that HHV-6A infection enhanced phosphorylation of the CREB family members CREB1 and activating transcription factor 1 (ATF1). Knockout (KO) of CREB1 or ATF1 enhanced viral gene expression and viral replication. The increase in viral yields in supernatants from ATF1-KO cells was greater than that in supernatants from CREB1-KO cells. Transcriptome sequencing (RNA-seq) analysis showed that sensors of the innate immune system were downregulated in ATF1-KO cells, and mRNAs of beta interferon (IFN-β) and IFN-regulated genes were reduced in these cells infected with HHV-6A. IFN-β treatment of ATF1-KO cells reduced progeny viral yields significantly, suggesting that the enhancement of viral replication was caused by a reduction of IFN-β. Taken together, our results suggest that ATF1 is activated during HHV-6A infection and restricts viral replication via IFN-β induction.IMPORTANCEHuman herpesvirus 6A (HHV-6A) is a ubiquitous herpesvirus implicated in Alzheimer’s disease, although its role in its pathogenesis has not been confirmed. Here, we showed that the transcription factor ATF1 restricts HHV-6A replication, mediated by IFN-β induction. Our study provides new insights into the role of ATF1 in innate viral immunity and reveals the importance of IFN-β for regulation of HHV-6A replication, which possibly impairs HHV-6A pathogenesis.