Control of Mitochondrial Membrane Permeabilization by Adenine Nucleotide Translocator Interacting with HIV-1 Viral Protein R and Bcl-2

doi:10.1084/jem.193.4.509

Published online 20 February 2001.

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© The Rockefeller University Press, 0022-1007/2001/2/509/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 509-520

Original Article

Control of Mitochondrial Membrane Permeabilization by Adenine Nucleotide Translocator Interacting with HIV-1 Viral Protein R and Bcl-2

Etienne Jacotot^a, Karine F. Ferri^a, Chahrazed El Hamel^a, Catherine Brenner^a,c, Sabine Druillennec^b, Johan Hoebeke^d, Pierre Rustin^e, Didier Métivier^a, Christine Lenoir^b, Maurice Geuskens^f, Helena L.A. Vieira^a, Markus Loeffler^a, Anne-Sophie Belzacq^c, Jean-Paul Briand^d, Naoufal Zamzami^a, Lena Edelman^g, Zhi Hua Xie^h, John C. Reed^h, Bernard P. Roques^b, and Guido Kroemer^a
^a Centre National de la Recherche Scientifique, UMR 1599, Institut Gustave Roussy, F-94805 Villejuif, France
^b Unité de Pharmacochimie Moléculaire et Structurale, Institut National de la Santé et de la Recherche Médicale U266, Centre National de la Recherche Scientifique, UMR 860, Université René Descartes (Paris V), 75006 France
^c Centre National de la Recherche Scientifique, UMR A6022, Université de Technologie de Compiègne, F-60205 Compiègne, France
^d Institut de Biologie Moleculaire et Cellulaire, Immunologie et Chimie Thérapeutiques, UPR 9021, Centre National de la Recherche Scientifique, 67084 Strasbourg, France
^e Unité de Recherche sur les Handicaps Génétiques de l'Enfant (Institut National de la Santé et de la Recherche Médicale U393), Hôpital des Enfants Malades-Necker, 75015 Paris, France
^f Free University of Brussels, B-1640 Rhode-St-Genese, Belgium
^g Laboratoire de Technologie Cellulaire, Institut Pasteur, 75015 Paris, France
^h The Burnham Institute, La Jolla, California 92037

Correspondence to: Guido Kroemer, CNRS-UMR 1599, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France. Tel:33-1-42-11-60-46

Viral protein R (Vpr), an apoptogenic accessory protein encodedby HIV-1, induces mitochondrial membrane permeabilization (MMP)via a specific interaction with the permeability transitionpore complex, which comprises the voltage-dependent anion channel(VDAC) in the outer membrane (OM) and the adenine nucleotidetranslocator (ANT) in the inner membrane. Here, we demonstratethat a synthetic Vpr-derived peptide (Vpr52-96) specificallybinds to the intermembrane face of the ANT with an affinityin the nanomolar range. Taking advantage of this specific interaction,we determined the role of ANT in the control of MMP. In planarlipid bilayers, Vpr52-96 and purified ANT cooperatively formlarge conductance channels. This cooperative channel formationrelies on a direct protein–protein interaction since itis abolished by the addition of a peptide corresponding to theVpr binding site of ANT. When added to isolated mitochondria,Vpr52-96 uncouples the respiratory chain and induces a rapidinner MMP to protons and NADH. This inner MMP precedes outerMMP to cytochrome c. Vpr52-96–induced matrix swellingand inner MMP both are prevented by preincubation of purifiedmitochondria with recombinant Bcl-2 protein. In contrast toKönig's polyanion (PA10), a specific inhibitor of the VDAC,Bcl-2 fails to prevent Vpr52-96 from crossing the mitochondrialOM. Rather, Bcl-2 reduces the ANT–Vpr interaction, asdetermined by affinity purification and plasmon resonance studies.Concomitantly, Bcl-2 suppresses channel formation by the ANT–Vprcomplex in synthetic membranes. In conclusion, both Vpr andBcl-2 modulate MMP through a direct interaction with ANT.

Key Words: ADP/ATP translocase, HIV, Vpr, mitochondria, Bcl-2

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