School of Biological Sciences, Seoul National University, 08826 Seoul, Republic of Korea.
Center for RNA Research, Institute for Basic Science, 08826 Seoul, Republic of Korea.
Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18619-18628. doi: 10.1073/pnas.1909314116. Epub 2019 Aug 26.
RNA represents a pivotal component of host-pathogen interactions. Human cytomegalovirus (HCMV) infection causes extensive alteration in host RNA metabolism, but the functional relationship between the virus and cellular RNA processing remains largely unknown. Through loss-of-function screening, we show that HCMV requires multiple RNA-processing machineries for efficient viral lytic production. In particular, the cellular RNA-binding protein Roquin, whose expression is actively stimulated by HCMV, plays an essential role in inhibiting the innate immune response. Transcriptome profiling revealed Roquin-dependent global down-regulation of proinflammatory cytokines and antiviral genes in HCMV-infected cells. Furthermore, using cross-linking immunoprecipitation (CLIP)-sequencing (seq), we identified IFN regulatory factor 1 (), a master transcriptional activator of immune responses, as a Roquin target gene. Roquin reduces IRF1 expression by directly binding to its mRNA, thereby enabling suppression of a variety of antiviral genes. This study demonstrates how HCMV exploits host RNA-binding protein to prevent a cellular antiviral response and offers mechanistic insight into the potential development of CMV therapeutics.
RNA 是宿主-病原体相互作用的关键组成部分。人类巨细胞病毒（HCMV）感染导致宿主 RNA 代谢发生广泛改变，但病毒与细胞 RNA 加工之间的功能关系在很大程度上仍不清楚。通过功能丧失筛选，我们表明 HCMV 需要多种 RNA 加工机制才能有效地进行病毒裂解生产。特别是细胞 RNA 结合蛋白 Roquin，其表达被 HCMV 积极刺激，在抑制先天免疫反应中发挥着重要作用。转录组谱分析显示，Roquin 依赖性地下调了 HCMV 感染细胞中促炎细胞因子和抗病毒基因的表达。此外，我们通过交联免疫沉淀（CLIP）-测序（seq）发现，干扰素调节因子 1（IRF1），一种免疫反应的主要转录激活因子，是 Roquin 的靶基因。Roquin 通过直接结合其 mRNA 来降低 IRF1 的表达，从而抑制多种抗病毒基因。这项研究展示了 HCMV 如何利用宿主 RNA 结合蛋白来阻止细胞抗病毒反应，并为 CMV 治疗药物的潜在开发提供了机制见解。
