The C-terminal moiety of HIV-1 Vpr induces cell death via a caspase-independent mitochondrial pathway.
Previous biochemical studies suggested that HIV-1-encoded Vpr may kill cells through an effect on the adenine nucleotide translocase (ANT), thereby causing mitochondrial membrane permeabilization (MMP). Here, we show that Vpr fails to activate caspases in conditions in which it induces cell killing. The knock-out of essential caspase-activators (Apaf-1 or caspase-9) or the knock-out of a mitochondrial caspase-independent death effector (AIF) does not abolish Vpr-mediated killing. In contrast, the cytotoxic effects of Vpr are reduced by transfection-enforced overexpression of two MMP-inhibitors, namely the endogenous protein Bcl-2 or the cytomegalovirus-encoded ANT-targeted protein vMIA. Vpr, which can elicit MMP through a direct effect on mitochondria, and HIV-1-Env, which causes MMP through an indirect pathway, exhibit additive (but not synergic) cytotoxic effects. In conclusion, it appears that Vpr induces apoptosis through a caspase-independent mitochondrial pathway.
Roumier
T
T
Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Vieira
H L A
HL
Castedo
M
M
Ferri
K F
KF
Boya
P
P
Andreau
K
K
Druillennec
S
S
Joza
N
N
Penninger
J M
JM
Roques
B
B
Kroemer
G
G
D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000378:metabolism; D005420:Flavoproteins / Q000502:physiology; D015686:Gene Products, env / Q000378:metabolism; D016336:Gene Products, vpr / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013234:Stem Cells; D014764:Viral Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D015686:Gene Products, env; D016336:Gene Products, vpr; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C420323:UL37 protein, Human herpesvirus 5; D014764:Viral Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; D020169:Caspases; D020782:Matrix Metalloproteinases