Activation of CXCL-8 Transcription by Hepatitis E Virus ORF-1 via AP-1

الملخص EN

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.