Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
Menzies Health Institute Queensland, School of Pharmacy and Medical Science, Griffith University, Southport, Queensland, Australia.
Vet Microbiol. 2022 Jan;264:109304. doi: 10.1016/j.vetmic.2021.109304. Epub 2021 Dec 13.
DEAD (Asp-Glu-Ala-Asp)-box RNA helicases (DDX) play important roles in viral infection, either as cytosolic viral nucleic acids sensors or as essential host factors for viral replication. In this study, we identified DDX56 as a positive regulator for encephalomyocarditis virus (EMCV) replication. EMCV infection promotes DDX56 expression via its viral proteins, VP3 and 3C. We showed that DDX56 overexpression promotes EMCV replication whereas its loss dampened EMCV replication. Consequently, knockdown of DDX56 increases type I interferon (IFN) expression during EMCV infection. We also showed that DDX56 interrupts IFN regulatory factor 3 (IRF3) phosphorylation and its nucleus translocation by directly targeting KPNA3 and KPNA4 in an EMCV-triggered MDA5 signaling activation cascade leading to the blockade of IFN-β production. Overall, we showed that DDX56 is a novel negative regulator of EMCV-mediated IFN-β responses and that DDX56 plays a critical role in EMCV replication. These findings reveal a novel strategy for EMCV to utilize a host factor to evade the host innate immune response and provide us new insight into the function of DDX56.
DEAD（天冬氨酸-谷氨酸-丙氨酸-天冬氨酸）盒 RNA 解旋酶（DDX）在病毒感染中发挥重要作用，既是细胞溶质病毒核酸传感器，也是病毒复制所必需的宿主因子。在本研究中，我们鉴定了 DDX56 是脑心肌炎病毒（EMCV）复制的正调控因子。EMCV 感染通过其病毒蛋白 VP3 和 3C 促进 DDX56 的表达。我们发现 DDX56 过表达促进 EMCV 复制，而其缺失则抑制 EMCV 复制。因此，DDX56 的敲低在 EMCV 感染期间增加了 I 型干扰素（IFN）的表达。我们还表明，DDX56 通过直接靶向 MDA5 信号激活级联反应中的 KPNA3 和 KPNA4 来中断 IFN 调节因子 3（IRF3）的磷酸化及其核易位，从而阻断 IFN-β 的产生。总的来说，我们表明 DDX56 是 EMCV 介导的 IFN-β 反应的新型负调控因子，DDX56 在 EMCV 复制中发挥关键作用。这些发现揭示了 EMCV 利用宿主因子逃避宿主先天免疫反应的新策略，并为我们提供了对 DDX56 功能的新见解。
