title: Activation of CXCL-8 Transcription by Hepatitis E Virus ORF-1 via AP-1.
abstract: Hepatitis E virus (HEV) is a small nonenveloped single-stranded positive-sense RNA virus and is one of the major causes for acute hepatitis worldwide. CXCL-8 is a small multifunctional proinflammatory chemokine. It was reported recently that HEV infection significantly upregulates CXCL-8 gene expression. In this study, we investigated the mechanism of HEV-induced CXCL-8 transcriptional activation. Using CXCL-8 promoter reporters of different lengths ranging from -1400 to -173, we showed that -173 promoter has the highest promoter activity in the presence of HEV genomic RNA, indicating that the -173 promoter contains sequences responsible for CXCL-8 activation by HEV. Ectopic expression of the ORF-1 protein can upregulate the -173 CXCL-8 promoter activity. In contrast, expression of the ORF-2 protein suppresses the CXCL-8 promoter activity and expression of the ORF-3 protein has no effect on the CXCL-8 promoter activity. We further showed that AP-1 is required for CXCL-8 activation because neither HEV genomic RNA nor the ORF-1 protein can upregulate the -173 CXCL-8 promoter in the absence of the AP-1 binding sequence. Taken together, our results showed that HEV and HEV ORF-1 protein activate the CXCL-8 promoter via AP-1. This novel function of HEV ORF-1 protein should contribute to our understanding of HEV-host interactions and HEV-associated pathogenesis.
authors.affiliation: VIDO-InterVac, Vaccinology and Immunotherapeutics Program, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E3.
authors.forename: Zhubing
authors.initials: Z
authors.lastname: Li
authors.affiliation: VIDO-InterVac, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E3 ; Henan Agricultural University, 95 Wenhua Road, Zhengzhou, Henan 450002, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: VIDO-InterVac, Vaccinology and Immunotherapeutics Program, Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada S7N 5E3.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D016752:Hepatitis E virus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D016209:Interleukin-8; D018808:Transcription Factor AP-1