Chandra Vivek, Kar-Roy Anindita, Kumari Sudha, Mayor Satyajit, Jameel Shahid
International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
J Virol. 2008 Jul;82(14):7100-10. doi: 10.1128/JVI.00403-08. Epub 2008 Apr 30.
The hepatitis E virus (HEV) causes acute viral hepatitis, but its characterization is hampered by the lack of an efficient in vitro infection system that can be used to study the effects of HEV proteins on cellular processes. Previous studies suggest that the viral ORF3 protein (pORF3) is essential for infection in vivo and is likely to modulate the host response. Here, we report that pORF3 localizes to early and recycling endosomes and causes a delay in the postinternalization trafficking of epidermal growth factor receptor (EGFR) to late endosomes/lysosomes. The cytoplasmic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) proteins require growth factor receptor endocytosis for their translocation from the cytoplasm to nucleus. Consequently, lower levels of pSTAT3 were found in the nuclei of ORF3-expressing Huh7 human hepatoma cells stimulated with EGF. This results in downregulation of the acute-phase response, a major determinant of inflammation in the host. We propose that through its effects on EGFR trafficking, pORF3 prolongs endomembrane growth factor signaling and promotes cell survival. The effects on STAT3 translocation would result in a reduced inflammatory response. Both of these events are likely to contribute positively to viral replication.
戊型肝炎病毒（HEV）可引起急性病毒性肝炎，但其特性研究因缺乏一种可用于研究HEV蛋白对细胞过程影响的高效体外感染系统而受阻。先前的研究表明，病毒ORF3蛋白（pORF3）对体内感染至关重要，且可能调节宿主反应。在此，我们报告pORF3定位于早期和循环内体，并导致表皮生长因子受体（EGFR）内化后向晚期内体/溶酶体的转运延迟。细胞质中的磷酸化信号转导子和转录激活子3（pSTAT3）蛋白需要生长因子受体内吞作用才能从细胞质转运至细胞核。因此，在用表皮生长因子（EGF）刺激的表达ORF3的Huh7人肝癌细胞的细胞核中发现pSTAT3水平较低。这导致急性期反应下调，而急性期反应是宿主炎症的主要决定因素。我们提出，通过对EGFR转运的影响，pORF3延长了内膜生长因子信号传导并促进细胞存活。对STAT3转运的影响将导致炎症反应减轻。这两个事件都可能对病毒复制产生积极作用。
