PDF(Pubmed)
Abstract：
Although the Hepatitis E virus (HEV) is an emerging global health burden, little is known about its interaction with the host cell. HEV genome encodes three proteins including the ORF2 capsid protein that is produced in different forms, the ORF2i protein which is the structural component of viral particles, and the ORF2g/c proteins which are massively secreted but are not associated with infectious material. We recently demonstrated that the endocytic recycling compartment (ERC) is hijacked by HEV to serve as a viral factory. However, host determinants involved in the subcellular shuttling of viral proteins to viral factories are unknown. Here, we demonstrate that the AP-1 adaptor complex plays a pivotal role in the targeting of ORF2i protein to viral factories. This complex belongs to the family of adaptor proteins that are involved in vesicular transport between the trans-Golgi network and early/recycling endosomes. An interplay between the AP-1 complex and viral protein(s) has been described for several viral lifecycles. In the present study, we demonstrated that the ORF2i protein colocalizes and interacts with the AP-1 adaptor complex in HEV-producing or infected cells. We showed that silencing or drug-inhibition of the AP-1 complex prevents ORF2i protein localization in viral factories and reduces viral production in hepatocytes. Modeling of the ORF2i/AP-1 complex also revealed that the S domain of ORF2i likely interacts with the σ1 subunit of AP-1 complex. Hence, our study identified for the first time a host factor involved in addressing HEV proteins (i.e. ORF2i protein) to viral factories.
摘要：
尽管戊型肝炎病毒（HEV）是一种新兴的全球健康负担，对其与宿主细胞的相互作用知之甚少。HEV基因组编码三种蛋白质，包括以不同形式产生的ORF2衣壳蛋白，ORF2i蛋白是病毒颗粒的结构成分，和大量分泌但与感染性物质无关的ORF2g/c蛋白。我们最近证明，HEV劫持了内吞回收室（ERC）作为病毒工厂。然而,参与病毒蛋白亚细胞穿梭到病毒工厂的宿主决定簇是未知的。这里,我们证明了AP-1衔接子复合物在ORF2i蛋白靶向病毒工厂中起着关键作用。该复合物属于衔接蛋白家族，该家族参与跨高尔基体网络和早期/再循环内体之间的囊泡运输。AP-1复合物和病毒蛋白之间的相互作用已经描述了几个病毒生命周期。在本研究中,我们证明了ORF2i蛋白在HEV产生或感染的细胞中与AP-1接头复合物共定位并相互作用。我们表明AP-1复合物的沉默或药物抑制可防止ORF2i蛋白在病毒工厂中的定位并减少肝细胞中的病毒产生。ORF2i/AP-1复合物的建模还显示ORF2i的S结构域可能与AP-1复合物的σ1亚基相互作用。因此，我们的研究首次确定了参与将HEV蛋白(即ORF2i蛋白)寻址到病毒工厂的宿主因子.
