Nucleic Acids Research Advance Access originally published online on April 8, 2008
Nucleic Acids Research 2008 36(9):3054-3064; doi:10.1093/nar/gkn111
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Nucleic Acids Research, 2008, Vol. 36, No. 9 3054-3064
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
The major form of hepatitis C virus alternate reading frame protein is suppressed by core protein expression
1Inserm, U748, 2Université Louis Pasteur, Strasbourg and 3Service d’Hépatogastroentérologie, Hôpitaux Universitaires de Strasbourg, F-67000, France
*To whom correspondence should be addressed. Tel: +33 3 90 24 37 41; Fax: +33 3 90 24 37 23; Email: catherine.schuster{at}viro-ulp.u-strasbg.fr
Received December 1, 2007. Revised February 27, 2008. Accepted February 28, 2008.
Hepatitis C virus (HCV) is a human RNA virus encoding 10 proteins in a single open reading frame. In the +1 frame, an ‘alternate reading frame’ (ARF) overlaps with the core protein-encoding sequence and encodes the ARF protein (ARFP). Here, we investigated the molecular regulatory mechanisms of ARFP expression in HCV target cells. Chimeric HCV-luciferase reporter constructs derived from the infectious HCV prototype isolate H77 were transfected into hepatocyte-derived cell lines. Translation initiation was most efficient at the internal AUG codon at position 86/88, resulting in the synthesis of a truncated ARFP named 86/88ARFP. Interestingly, 86/88ARFP synthesis was markedly enhanced in constructs containing an inactivated core protein reading frame. This enhancement was reversed by co-expression of core protein in trans, demonstrating suppression of ARFP synthesis by HCV core protein. In conclusion, our results indicate that translation of ARFP occurs mainly by alternative internal initiation at position 86/88 and is regulated by HCV core protein expression. The suppression of ARFP translation by HCV core protein suggests that ARFP expression is inversely linked to the level of viral replication. These findings define key mechanisms regulating ARFP expression and set the stage for further studies addressing the function of ARFP within the viral life cycle.
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