The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4.
The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4.
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DOI：
10.1371/journal.pone.0022412
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Jameel S
中科院分区：
文献类型：
--
作者：
Chandra V;Holla P;Ghosh D;Chakrabarti D;Padigaru M;Jameel S
戊型肝炎病毒（HEV）是一种小RNA病毒，是急性戊型肝炎的病因。戊型肝炎病毒的开放阅读框3蛋白（pORF 3）是一种多效性调节蛋白，有助于病毒感染的建立、繁殖和进展。然而，这种蛋白质的整体细胞效应仍有待探索。在缺乏传统的体外病毒感染系统或有效的复制子系统的情况下，我们构建了一个基于腺病毒的ORF3蛋白表达系统，以研究其对宿主细胞基因表达的影响。我们用表达pORF3的重组腺病毒感染Huh7肝癌细胞，并进行基于微阵列的基因表达分析。在pORF3表达细胞中下调的几个基因被发现受到肝脏富集的肝细胞核因子4（HNF 4）的调节，该因子调节肝细胞特异性基因表达。虽然HNF4定位于细胞核，但其磷酸化导致HNF4的核定位受损。在这里，我们报告说，pORF3增加HNF4磷酸化通过ERK和Akt激酶，这导致受损的HNF4核转位，随后下调HNF4响应基因在pORF3表达细胞。我们认为pORF3对几个肝细胞特异性基因的调控将为病毒的复制和致病创造有利的环境。
The hepatitis E virus (HEV) is a small RNA virus and the cause of acute viral hepatitis E. The open reading frame 3 protein (pORF3) of HEV appears to be a pleiotropic regulatory protein that helps in the establishment, propagation and progression of viral infection. However, the global cellular effects of this protein remain to be explored. In the absence of traditional in vitro viral infection systems or efficient replicon systems, we made an adenovirus based ORF3 protein expression system to study its effects on host cell gene expression. We infected Huh7 hepatoma cells with recombinant adenoviruses expressing pORF3 and performed microarray-based gene expression analyses. Several genes down regulated in pORF3-expressing cells were found to be under regulation of the liver-enriched hepatocyte nuclear factor 4 (HNF4), which regulates hepatocyte-specific gene expression. While HNF4 localizes to the nucleus, its phosphorylation results in impaired nuclear localization of HNF4. Here we report that pORF3 increases HNF4 phosphorylation through the ERK and Akt kinases, which results in impaired nuclear translocation of HNF4 and subsequently the down modulation of HNF4-responsive genes in pORF3-expressing cells. We propose that modulation of several hepatocyte specific genes by pORF3 will create an environment favorable for viral replication and pathogenesis.
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影响因子：
5.9
作者：
KHUROO, MS;TELI, MR;KHUROO, MI
通讯作者：
KHUROO, MI
影响因子：
5.4
作者：
Emerson, Suzanne U.;Nguyen, Hanh;Purcell, Robert H.
通讯作者：
Purcell, Robert H.
肝炎病毒ORF3蛋白可保护细胞免受线粒体去极化和死亡的影响。
影响因子：
4.8
作者：
Moin, Syed Mohammad;Panteva, Milena;Jameel, Shahid
通讯作者：
Jameel, Shahid
影响因子：
4.8
作者：
Korkaya, H;Jameel, S;Sahal, D
通讯作者：
Sahal, D
影响因子：
12.7
作者：
Biswas, S. M.;Kar, S.;Ghosh, D.
通讯作者：
Ghosh, D.