The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore.
Viral protein R (Vpr) encoded by HIV-1 is a facultative inducer of apoptosis. When added to intact cells or purified mitochondria, micromolar and submicromolar doses of synthetic Vpr cause a rapid dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), as well as the mitochondrial release of apoptogenic proteins such as cytochrome c or apoptosis inducing factor. The same structural motifs relevant for cell killing are responsible for the mitochondriotoxic effects of Vpr. Both mitochondrial and cytotoxic Vpr effects are prevented by Bcl-2, an inhibitor of the permeability transition pore complex (PTPC). Coincubation of purified organelles revealed that nuclear apoptosis is only induced by Vpr when mitochondria are present yet can be abolished by PTPC inhibitors. Vpr favors the permeabilization of artificial membranes containing the purified PTPC or defined PTPC components such as the adenine nucleotide translocator (ANT) combined with Bax. Again, this effect is prevented by addition of recombinant Bcl-2. The Vpr COOH terminus binds purified ANT, as well as a molecular complex containing ANT and the voltage-dependent anion channel (VDAC), another PTPC component. Yeast strains lacking ANT or VDAC are less susceptible to Vpr-induced killing than control cells yet recover Vpr sensitivity when retransfected with yeast ANT or human VDAC. Hence, Vpr induces apoptosis via a direct effect on the mitochondrial PTPC.
Jacotot
E
E
Centre National de la Recherche Scientifique, F-94801 Villejuif, France.
Ravagnan
L
L
Loeffler
M
M
Ferri
K F
KF
Vieira
H L
HL
Zamzami
N
N
Costantini
P
P
Druillennec
S
S
Hoebeke
J
J
Briand
J P
JP
Irinopoulou
T
T
Daugas
E
E
Susin
S A
SA
Cointe
D
D
Xie
Z H
ZH
Reed
J C
JC
Roques
B P
BP
Kroemer
G
G
D017209:Apoptosis; D002474:Cell-Free System; D016336:Gene Products, vpr / Q000737:chemistry / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000502:physiology*; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016336:Gene Products, vpr; D019253:Proto-Oncogene Proteins c-bcl-2; D054325:vpr Gene Products, Human Immunodeficiency Virus