异质核核糖核蛋白(hnRNPA2B1)是hnRNP复合物的关键组成部分,涉及真核细胞中的RNA调节,并且据报道,它也参与了戊型肝炎病毒的复制。甲型流感病毒,和乙型肝炎病毒。然而,目前尚不清楚hnRNPA2B1在病毒复制中的作用在RNA病毒中是否保守,以及hnRNPA2B1在RNA病毒复制中的作用机制是什么。在这项研究中,我们首先使用了严重发热伴血小板减少综合征病毒(SFTSV),一种蜱传RNA病毒,可引起严重的病毒性出血热以及其他RNA病毒,包括VSV-GFP,SeV,EV71和ZIKV证明敲除hnRNPA2B1基因抑制病毒RNA复制,hnRNPA2B1的过表达可以恢复所有测试RNA病毒的RNA水平。这些结果表明hnRNPA2B1上调病毒复制在RNA病毒中是保守的。接下来,我们证明hnRNPA2B1在RNA病毒感染包括SFTSV,VSV-GFP,SeV,EV71和ZIKV,表明hnRNPA2B1从细胞核到细胞质的易位对于RNA病毒复制至关重要。然后我们以SFTSV为模子来论证hnRNPA2B1在增进RNA病毒复制中的机制。我们发现SFTSV核蛋白的过表达也可以导致hnRNPA2B1从细胞核转位到细胞质,并且SFTSVNP与hnRNPA2B1的RNA识别基序1结构域相互作用。我们进一步证明了hnRNPA2B1与SFTSVRNA的5'UTR相互作用。总之,我们发现,hnRNPA2B1上调病毒RNA复制在RNA病毒中是保守的;hnRNPA2B1促进SFTSV病毒RNA复制的机制是SFTSVNP与hnRNPA2B1相互作用,将其保留在细胞质中,hnRNPA2B1与SFTSVRNA的5'UTR相互作用以促进病毒RNA复制。IMPORTANCE重症发热伴血小板减少综合征病毒(SFTSV)是一种蜱传RNA病毒,死亡率高达30%。在这项研究中,我们首先使用SFTSV作为模型来证明hnRNPA2B1在病毒复制中的作用在SFTSV中是保守的.然后我们使用了其他RNA病毒,包括VSV-GFP,SeV,EV71和ZIKV,重复实验,并在所有测试的RNA病毒中证明与SFTSV相同的结果。通过敲除hnRNPA2B1基因,SFTSVRNA复制被抑制,hnRNPA2B1的过表达恢复了SFTSV和其他测试RNA病毒的RNA水平。我们揭示了SFTSV核蛋白与hnRNPA2B1相互作用并将其保留在细胞质中的新机制。这种相互作用通过与SFTSVRNA的5'UTR结合来促进病毒RNA复制。研究结果表明,靶向hnRNPA2B1可能是开发广谱抗病毒疗法的潜在策略,鉴于其在不同RNA病毒中的保守作用。这项研究提供了对RNA病毒复制机制的重要见解,并突出了抗病毒干预的潜在目标。
The heterogeneous nuclear ribonucleoprotein (hnRNP A2B1) is a key component of the hnRNP complex involving RNA modulation in eukaryotic cells and it has also been reported to be involved in the replication of the hepatitis E virus, influenza A virus, and hepatitis B virus. However, it is not clear whether the role of the hnRNP A2B1 in viral replication is conserved among RNA viruses and what is the mechanism of hnRNP A2B1 in RNA virus replication. In this study, we first used severe fever with thrombocytopenia syndrome virus (SFTSV), a tick-borne RNA virus that causes a severe viral hemorrhagic fever as well as other RNA viruses including VSV-GFP, SeV, EV71, and ZIKV to demonstrate that knockout hnRNPA2B1 gene inhibited viral RNA replication and overexpression of hnRNP A2B1 could restore the RNA levels of all tested RNA viruses. These results suggest that hnRNPA2B1 upregulation of viral replication is conserved among RNA viruses. Next, we demonstrated that hnRNP A2B1 was translocated from the nucleus to the cytoplasm under RNA virus infection including SFTSV, VSV-GFP, SeV, EV71, and ZIKV, suggesting translocation of hnRNP A2B1 from the nucleus to the cytoplasm is crucial for RNA virus replication. We then used SFTSV as a model to demonstrate the mechanism of hnRNP A2B1 in the promotion of RNA virus replication. We found that overexpression of SFTSV
nucleoprotein can also cause hnRNP A2B1 translocation from the nucleus to the cytoplasm and that the SFTSV NP interacted with the RNA recognition motif 1 domain of hnRNP A2B1. We further demonstrated that the hnRNP A2B1 interacted with the 5\' UTR of SFTSV RNA. In conclusion, we revealed that the hnRNP A2B1 upregulation of viral RNA replication is conserved among RNA viruses; the mechanism of hnRNP A2B1 in promotion of SFTSV viral RNA replication is that SFTSV NP interacted with the hnRNPA2B1 to retain it in the cytoplasm where the hnRNP A2B1 interacted with the 5\' UTR of SFTSV RNA to promote the viral RNA replication.IMPORTANCESevere fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne RNA virus with a high mortality rate of up to 30%. In this study, we first used SFTSV as a model to demonstrate that the role of hnRNPA2B1 in viral replication is conserved in SFTSV. Then we used other RNA viruses, including VSV-GFP, SeV, EV71, and ZIKV, to repeat the experiment and demonstrated the same results as SFTSV in all tested RNA viruses. By knocking out the hnRNPA2B1 gene, SFTSV RNA replication was inhibited, and overexpression of hnRNPA2B1 restored RNA levels of SFTSV and other tested RNA viruses. We revealed a novel mechanism where the SFTSV
nucleoprotein interacts with hnRNPA2B1, retaining it in the cytoplasm. This interaction promotes viral RNA replication by binding to the 5\' UTR of SFTSV RNA. The findings suggest that targeting hnRNPA2B1 could be a potential strategy for developing broad-spectrum antiviral therapies, given its conserved role across different RNA viruses. This research provides significant insights into the replication mechanisms of RNA viruses and highlights potential targets for antiviral interventions.