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Journal of Virology, July 2008, p. 7100-7110, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00403-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Hepatitis E Virus ORF3 Protein Modulates Epidermal Growth Factor Receptor Trafficking, STAT3 Translocation, and the Acute-Phase Response{triangledown}

Vivek Chandra,1,{dagger} Anindita Kar-Roy,1,{dagger} Sudha Kumari,2 Satyajit Mayor,2* and Shahid Jameel1*

International Centre for Genetic Engineering and Biotechnology, New Delhi, India,1 National Centre for Biological Sciences, Bangalore, India2

Received 25 February 2008/ Accepted 18 April 2008

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.

* Corresponding author. Mailing address for S. Jameel: Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110 067, India. Phone: 91 11 26177357, ext 253. Fax: 91 11 26162316. E-mail: shahid{at}icgeb.res.in. Mailing address for S. Mayor: National Centre for Biological Sciences, UAS-GKVK Campus, Bellary Road, Bangalore 560 065, India. Phone: 91 80 23636421. Fax: 91 80 23636662. E-mail: mayor{at}ncbs.res.in

{triangledown} Published ahead of print on 30 April 2008.

{dagger} V.C. and A.K.-R. contributed equally to this work.

Journal of Virology, July 2008, p. 7100-7110, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.00403-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kalia, M., Chandra, V., Rahman, S. A., Sehgal, D., Jameel, S. (2009). Heparan Sulfate Proteoglycans Are Required for Cellular Binding of the Hepatitis E Virus ORF2 Capsid Protein and for Viral Infection. J. Virol. 83: 12714-12724 [Abstract] [Full Text]  
  • Ratra, R., Kar-Roy, A., Lal, S. K. (2009). ORF3 protein of hepatitis E virus interacts with the B{beta} chain of fibrinogen resulting in decreased fibrinogen secretion from HuH-7 cells. J. Gen. Virol. 90: 1359-1370 [Abstract] [Full Text]  


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