Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Biochem Biophys Res Commun. 2019 Jul 30;515(3):403-409. doi: 10.1016/j.bbrc.2019.05.083. Epub 2019 May 31.
Dengue virus (DENV) infection is a public health problem worldwide. To establish infection in host cells, DENV require host cellular mechanism to suppress and evade innate immunity for their replication. In this study, Ccr4-Not complex genes were screened by using RNAi approach in DENV-infected A549 and Huh7 cells. We found that CNOT2 plays a proviral role in DENV infection. The expression level of CNOT2 was up-regulated in DENV-infected cells. Down-regulation of CNOT2 significantly reduced DENV RNA replication and protein synthesis. Mechanism study showed that CNOT2 knockdown enhanced JAK-STAT antiviral signaling during DENV infection. Further analysis revealed that CNOT2 negatively modulated IFN-Independent Non-Canonical JAK/STAT pathway by accelerating the mRNA decay of JAK1 and STAT1 via its interaction with CNOT6/6L and CNOT7/8 deadenylases. Overall, these results demonstrate that CNOT2 is a novel negative regulator of the JAK-STAT pathway and supports DENV infection.
登革热病毒（DENV）感染是一个全球性的公共卫生问题。为了在宿主细胞中建立感染，DENV 需要宿主细胞机制来抑制和逃避先天免疫以进行复制。在这项研究中，我们使用 RNAi 方法在感染 DENV 的 A549 和 Huh7 细胞中筛选了 Ccr4-Not 复合物基因。我们发现 CNOT2 在 DENV 感染中起促进病毒作用。在感染 DENV 的细胞中，CNOT2 的表达水平上调。CNOT2 的下调显著降低了 DENV RNA 复制和蛋白合成。机制研究表明，CNOT2 通过与 CNOT6/6L 和 CNOT7/8 脱腺苷酶相互作用加速 JAK1 和 STAT1 的 mRNA 降解，从而增强 DENV 感染期间的 JAK-STAT 抗病毒信号。进一步分析表明，CNOT2 通过其与 CNOT6/6L 和 CNOT7/8 脱腺苷酶的相互作用，负调控 IFN 非依赖性非经典 JAK/STAT 通路，从而负调控 JAK-STAT 通路。总的来说，这些结果表明 CNOT2 是 JAK-STAT 通路的新型负调节剂，并支持 DENV 感染。
