Open Reading Frame 3 of Genotype 1 Hepatitis E Virus Inhibits Nuclear Factor-kappa appa B Signaling Induced by Tumor Necrosis Factor-alpha in Human A549 Lung Epithelial Cells

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	Open Reading Frame 3 of Genotype 1 Hepatitis E Virus Inhibits Nuclear Factor-kappa appa B Signaling Induced by Tumor Necrosis Factor-alpha in Human A549 Lung Epithelial Cells
	Xu, Jian ; Wu, Fan ; Tian, Deying ; Wang, Jingjing ; Zheng, Zizheng ; Xia, Ningshao ; Zheng ZZ(郑子峥) ; Xia NS(夏宁邵)
刊名	http://dx.doi.org/10.1371/journal.pone.0100787
	2014-06-24
关键词	ENDOPLASMIC-RETICULUM STRESS UNFOLDED PROTEIN RESPONSE HEV INFECTION ACTIVATION A20 UBIQUITINATION INFLAMMATION TRANSMISSION PATHOGENESIS SUPERFAMILY
英文摘要	Hepatitis E virus (HEV) is one of the primary causative agents of acute hepatitis, and represents a major cause of severe public health problems in developing countries. The pathogenesis of HEV is not well characterized, however, primarily due to the lack of well-defined cell and animal models. Here, we investigated the effects of genotype 1 HEV open reading frame 3 (ORF3) on TNF-alpha-induced nucleus factor-kappa appa B (NF-kappa B) signaling. Human lung epithelial cells (A549) were transiently transfected with ORF3 containing plasmids. These cells were then stimulated with TNF-alpha and the nucleus translocation of the p65 NF-kappa B subunit was assessed using western blot and laser confocal microscopy. DNA-binding activity of p65 was also examined using electrophoretic mobility shift assay (EMSA), and the suppression of NF-kappa B target genes were detected using real-time RT-PCR and ELISA. These results enabled us to identify the decreased phosphorylation levels of IKB alpha. We focused on the gene of negative regulation of NF-kappa B, represented by TNF-alpha-induced protein 3 (TNFAIP3, also known as A20). Reducing the levels of A20 with siRNAs significantly enhances luciferase activation of NF-kappa B. Furthermore, HEV ORF3 regulated A20 primarily via activating transcription factor 6 (ATF6), involved in unfolded protein response (UPR), resulting in the degradation or inactivation of the receptor interacting protein 1 (RIP1), a major upstream activator of IKB kinase compounds (IKKs). Consequently, the phosphorylation of IKBa and the nucleus translocation of p65 are blocked, which contributes to diminished NF-kappa B DNA-binding activation and NF-kappa B-dependent gene expression. The findings suggest that genotype 1 HEV, through ORF3, may transiently activate NF-kappa B through UPR in early stage, and subsequently inhibit TNF-alpha-induced NF-kappa B signaling in late phase so as to create a favorable virus replication environment.
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/87579]
专题	公共卫生－已发表论文
推荐引用方式 GB/T 7714	Xu, Jian,Wu, Fan,Tian, Deying,et al. Open Reading Frame 3 of Genotype 1 Hepatitis E Virus Inhibits Nuclear Factor-kappa appa B Signaling Induced by Tumor Necrosis Factor-alpha in Human A549 Lung Epithelial Cells[J]. http://dx.doi.org/10.1371/journal.pone.0100787,2014.
APA	Xu, Jian.,Wu, Fan.,Tian, Deying.,Wang, Jingjing.,Zheng, Zizheng.,...&夏宁邵.(2014).Open Reading Frame 3 of Genotype 1 Hepatitis E Virus Inhibits Nuclear Factor-kappa appa B Signaling Induced by Tumor Necrosis Factor-alpha in Human A549 Lung Epithelial Cells.http://dx.doi.org/10.1371/journal.pone.0100787.
MLA	Xu, Jian,et al."Open Reading Frame 3 of Genotype 1 Hepatitis E Virus Inhibits Nuclear Factor-kappa appa B Signaling Induced by Tumor Necrosis Factor-alpha in Human A549 Lung Epithelial Cells".http://dx.doi.org/10.1371/journal.pone.0100787 (2014).