An anti-apoptotic viral protein that recruits Bax to mitochondria.
The viral mitochondria-localized inhibitor of apoptosis (vMIA), encoded by the UL37 gene of human cytomegalovirus, inhibits apoptosis-associated mitochondrial membrane permeabilization by a mechanism different from that of Bcl-2. Here we show that vMIA induces several changes in Bax that resemble those found in apoptotic cells yet take place in unstimulated, non-apoptotic vMIA-expressing cells. These changes include the constitutive localization of Bax at mitochondria, where it associates tightly with the mitochondrial membrane, forming high molecular weight aggregates that contain vMIA. vMIA recruits Bax to mitochondria but delays relocation of caspase-8-activated truncated Bid-green fluorescent protein (GFP) (t-Bid-GFP) to mitochondria. The ability of vMIA and its deletion mutants to associate with Bax and to induce relocation of Bax to mitochondria correlates with their anti-apoptotic activity and with their ability to suppress mitochondrial membrane permeabilization. Taken together, our data indicate that vMIA blocks apoptosis via its interaction with Bax. vMIA neutralizes Bax by recruiting it to mitochondria and "freezing" its pro-apoptotic activity. These data unravel a novel strategy of subverting an intrinsic pathway of apoptotic signaling.
Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Delphine
D
Poncet
Nathanael
N
Larochette
Anne-Laure
AL
Pauleau
Patricia
P
Boya
Abdel-Ali
AA
Jalil
Pierre-Francois
PF
Cartron
Francois
F
Vallette
Céline
C
Schnebelen
Laura M
LM
Bartle
Anna
A
Skaletskaya
David
D
Boutolleau
Jean-Claude
JC
Martinou
Victor S
VS
Goldmacher
Guido
G
Kroemer
Naoufal
N
Zamzami
D000818:Animals; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002474:Cell-Free System; D002478:Cells, Cultured; D002850:Chromatography, Gel; D045304:Cytochromes c / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000502:physiology*; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection; D014764:Viral Proteins / Q000096:biosynthesis* / Q000378:metabolism* / Q000502:physiology*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; D017874:Immediate-Early Proteins; D008164:Luminescent Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C420323:UL37 protein, Human herpesvirus 5; D014764:Viral Proteins; D051028:bcl-2-Associated X Protein; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases