Xu Peng, Tong Wei, Kuo Chen-Yen, Chen Han-Hsiang, Wang Robert Y L
Xiangyang No. 1 People's Hospital and Hubei University of Medicine; Hubei Province, China.
Department of Clinical Laboratory, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China.
Microbes Infect. 2023 Nov-Dec;25(8):105220. doi: 10.1016/j.micinf.2023.105220. Epub 2023 Sep 19.
Enterovirus A71 (EV-A71) is transmitted through the respiratory tract, gastrointestinal system, and fecal-oral routes. The main symptoms caused by EV-A71 are hand, foot, and mouth disease (HFMD) or vesicular sore throat. Upf1 (Up-frameshift protein 1) was reported to degrade mRNA containing early stop codons, known as nonsense-mediated decay (NMD). Upf1 is also involved in the NMD mechanism as a host factor detrimental to viral replication. In this study, we dissected the potential roles of Upf1 in the EV-A71-infected cells. Upf1 was virulently down-regulated in three different EV-A71-infected cells, RD, Hela, and 293T, implying that Upf1 is a host protein unfavorable for EV-A71 replication. Knockdown of Upf1 protein resulted in increased viral RNA expression and production of progeny virus, and conversely, overexpression of Upf1 protein resulted in decreased viral RNA expression and production of progeny virus. Importantly, we observed increased RNA levels of asparagine synthetase (ASNS), one of the indicator substrates for the NMD mechanism, which indirectly suggests that EV-A71 infection of cells suppresses NMD activity in the host. The results shown in this study are useful for subsequent analysis of the relationship between the NMD/Upf1 mechanism and other picornaviruses, which may lead to the development of anti-picornavirus drugs.
肠道病毒A71（EV - A71）通过呼吸道、胃肠道系统和粪口途径传播。EV - A71引起的主要症状是手足口病（HFMD）或疱疹性咽峡炎。据报道，Upf1（移码蛋白1）可降解含有提前终止密码子的mRNA，即无义介导的衰变（NMD）。Upf1作为一种对病毒复制有害的宿主因子，也参与NMD机制。在本研究中，我们剖析了Upf1在EV - A71感染细胞中的潜在作用。在三种不同的EV - A71感染细胞RD、Hela和293T中，Upf1被显著下调，这意味着Upf1是一种不利于EV - A71复制的宿主蛋白。敲低Upf1蛋白导致病毒RNA表达增加和子代病毒产生，相反，过表达Upf1蛋白导致病毒RNA表达减少和子代病毒产生。重要的是，我们观察到天冬酰胺合成酶（ASNS）的RNA水平升高，ASNS是NMD机制的指示底物之一，这间接表明细胞的EV - A71感染会抑制宿主中的NMD活性。本研究结果有助于后续分析NMD/Upf1机制与其他小RNA病毒之间的关系，这可能会推动抗小RNA病毒药物的开发。
