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Journal of Virology, April 2005, p. 5163-5173, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5163-5173.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Proline-Rich Region in the Coxsackievirus 3A Protein Is Required for the Protein To Inhibit Endoplasmic Reticulum-to-Golgi Transport

Els Wessels,1 Daniël Duijsings,1 Richard A. Notebaart,2 Willem J. G. Melchers,1 and Frank J. M. van Kuppeveld1*

Department of Medical Microbiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen,1 Center for Molecular and Biomolecular Informatics, University of Nijmegen, Nijmegen, The Netherlands2

Received 13 July 2004/ Accepted 17 November 2004

The ability of the 3A protein of coxsackievirus B (CVB) to inhibit protein secretion was investigated for this study. Here we show that the ectopic expression of CVB 3A blocked the transport of both the glycoprotein of vesicular stomatitis virus, a membrane-bound secretory marker, and the alpha-1 protease inhibitor, a luminal secretory protein, at a step between the endoplasmic reticulum (ER) and the Golgi complex. CVB 3A contains a conserved proline-rich region in its N terminus. The importance of this proline-rich region was investigated by introducing Pro-to-Ala substitutions. The mutation of Pro19 completely abolished the ability of 3A to inhibit ER-to-Golgi transport. The mutation of Pro14, Pro17, or Pro20 also impaired this ability, but to a lesser extent. The mutation of Pro18 had no effect. We also investigated the possible importance of this proline-rich region for the function of 3A in viral RNA replication. To this end, we introduced the Pro-to-Ala mutations into an infectious cDNA clone of CVB3. The transfection of cells with in vitro-transcribed RNAs of these clones gave rise to mutant viruses that replicated with wild-type characteristics. We concluded that the proline-rich region in CVB 3A is required for its ability to inhibit ER-to-Golgi transport, but not for its function in viral RNA replication. The functional relevance of the proline-rich region is discussed in light of the proposed structural model of 3A.

* Corresponding author. Mailing address: Department of Medical Microbiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: (31) 24 3617574. Fax: (31) 24 3540216. E-mail: f.vankuppeveld{at}ncmls.ru.nl.

Journal of Virology, April 2005, p. 5163-5173, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5163-5173.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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