Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA.
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.
Poncet
Delphine
D
Centre National de la Recherche Scientifique, FRE2939, Institut Gustave Roussy, F-94805 Villejuif, France.
Pauleau
Anne-Laure
AL
Szabadkai
Gyorgy
G
Vozza
Angelo
A
Scholz
Sebastian R
SR
Le Bras
Morgane
M
Brière
Jean-Jacques
JJ
Jalil
Abdelali
A
Le Moigne
Ronan
R
Brenner
Catherine
C
Hahn
Gabriele
G
Wittig
Ilka
I
Schägger
Hermann
H
Lemaire
Christophe
C
Bianchi
Katiuscia
K
Souquère
Sylvie
S
Pierron
Gerard
G
Rustin
Pierre
P
Goldmacher
Victor S
VS
Rizzuto
Rosario
R
Palmieri
Ferdinando
F
Kroemer
Guido
G
D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D003588:Cytopathogenic Effect, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011108:Polymers / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics
D000199:Actins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D024101:Mitochondrial Proteins; D011108:Polymers; C420323:UL37 protein, Human herpesvirus 5; D014764:Viral Proteins; D051028:bcl-2-Associated X Protein; D000255:Adenosine Triphosphate