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J. Biol. Chem., Vol. 281, Issue 20, 14144-14150, May 19, 2006

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The Coxsackievirus 2B Protein Increases Efflux of Ions from the Endoplasmic Reticulum and Golgi, thereby Inhibiting Protein Trafficking through the Golgi^*

Arjan S. de Jong, Henk-Jan Visch, Fabrizio de Mattia, Michiel M. van Dommelen, Herman G. Swarts, Tomas Luyten^¶, Geert Callewaert^¶, Willem J. Melchers, Peter H. Willems, and Frank J. van Kuppeveld¹

From the Departments of Medical Microbiology and Biochemistry, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands and ^¶Department of Physiology, Catholic University Leuven, B-3000 Leuven, Belgium

Coxsackievirus infection leads to a rapid reduction of the filling state of the endoplasmic reticulum (ER) and Golgi Ca²⁺ stores. The coxsackievirus 2B protein, a small membrane protein that localizes to the Golgi and to a lesser extent to the ER, has been proposed to play an important role in this effect by forming membrane-integral pores, thereby increasing the efflux of Ca²⁺ from the stores. Here, evidence is presented that supports this idea and that excludes the possibility that 2B reduces the uptake of Ca²⁺ into the stores. Measurement of intra-organelle-free Ca²⁺ in permeabilized cells revealed that the ability of 2B to reduce the Ca²⁺ filling state of the stores was preserved at steady ATP. Biochemical analysis in a cell-free system further showed that 2B had no adverse effect on the activity of the sarco/endoplasmic reticulum calcium ATPase, the Ca²⁺-ATPase that transports Ca²⁺ from the cytosol into the stores. To investigate whether 2B specifically affects Ca²⁺ homeostasis or other ion gradients, we measured the lumenal Golgi pH. Expression of 2B resulted in an increased Golgi pH, indicative for the efflux of H⁺ from the Golgi lumen. Together, these data support a model that 2B increases the efflux of ions from the ER and Golgi by forming membrane-integral pores. We have demonstrated that a major consequence of this activity is the inhibition of protein trafficking through the Golgi complex.

Received for publication, November 1, 2005 , and in revised form, March 7, 2006.

^* This work was partly supported by grants from the Netherlands Organization for Scientific Research (NWO-VIDI-917.46.305), the M. W. Beijerink Virology Fund from the Royal Netherlands Academy of Sciences, and the European Communities (INTAS 2012). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: 31-24-3617574; Fax: 31-24-3614666; E-mail: f.vankuppeveld{at}ncmls.ru.nl.

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