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Published online 18 September 2006. doi:10.1083/jcb.200604069
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 7, 985-996
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*Cytomegalovirus Infections
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Article

Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA



Delphine Poncet1, Anne-Laure Pauleau1, Gyorgy Szabadkai2, Angelo Vozza3, Sebastian R. Scholz3, Morgane Le Bras4, Jean-Jacques Brière5, Abdelali Jalil6, Ronan Le Moigne7, Catherine Brenner4, Gabriele Hahn8, Ilka Wittig9, Hermann Schägger9, Christophe Lemaire4, Katiuscia Bianchi2, Sylvie Souquère10, Gerard Pierron10, Pierre Rustin5, Victor S. Goldmacher11, Rosario Rizzuto2, Ferdinando Palmieri3, and Guido Kroemer1

1 Centre National de la Recherche Scientifique, FRE2939, Institut Gustave Roussy, F-94805 Villejuif, France
2 Department of Experimental and Diagnostic Medicine, Section of General Pathology, University of Ferrara, Ferrara 44100, Italy
3 Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy
4 Centre National de la Recherche Scientifique, UMR8159, Université de Versailles-St. Quentin, 78035 Versailles Cedex, France
5 Institut National de la Santé et de la Recherche Médicale U676, Hopital Robert Debré, 75019 Paris, France
6 Service Commun de Microscopie Confocale, Institut Gustave Roussy, 7 UMR8113, ENS Cachan, 94230 Cachan
8 Max von Pettenkofer Institut, Universitaet Muenchen, 80336 Muenchen, Germany
9 Molekular Bioenergetik, Zentrum der Biologischen Chemie, Universätsklinikum Frankfurt, D-60590 Frankfurt, Germany
10 Institut André Lwoff, UPR-1983, Laboratoire Replication de l'ADN et Ultrastructure du Noyau, 94801 Villejuif, France
11 ImmunoGen Inc., Cambridge, MA 02139

Correspondence to Guido Kroemer: kroemer{at}igr.fr

Replication of human cytomegalovirus (CMV) requires the expression of the viral mitochondria–localized inhibitor of apoptosis (vMIA). vMIA inhibits apoptosis by recruiting Bax to mitochondria, resulting in its neutralization. We show that vMIA decreases cell size, reduces actin polymerization, and induces cell rounding. As compared with vMIA-expressing CMV, vMIA-deficient CMV, which replicates in fibroblasts expressing the adenoviral apoptosis suppressor E1B19K, induces less cytopathic effects. These vMIA effects can be separated from its cell death–inhibitory function because vMIA modulates cellular morphology in Bax-deficient cells. Expression of vMIA coincided with a reduction in the cellular adenosine triphosphate (ATP) level. vMIA selectively inhibited one component of the ATP synthasome, namely, the mitochondrial phosphate carrier. Exposure of cells to inhibitors of oxidative phosphorylation produced similar effects, such as an ATP level reduced by 30%, smaller cell size, and deficient actin polymerization. Similarly, knockdown of the phosphate carrier reduced cell size. Our data suggest that the cytopathic effect of CMV can be explained by vMIA effects on mitochondrial bioenergetics.

D. Poncet and A.-L. Pauleau contributed equally to this paper.

Abbreviations used in this paper: ANT, adenine nucleotide translocase; CMV, cytomegalovirus; EA, early antigen; ECE, early cytopathic effect; FSC, forward scatter channel; IEA, immediate early antigen; LCE, late cytopathic effect; MOMP, mitochondrial outer membrane permeabilization; PiC, phosphate inorganic carrier; RC, respiratory control; vMIA, viral mitochondria–localized inhibitor of apoptosis.


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