The myxoma poxvirus protein, M11L, prevents apoptosis by direct interaction with the mitochondrial permeability transition pore.
M11L, an antiapoptotic protein essential for the virulence of the myxoma poxvirus, is targeted to mitochondria and prevents the loss of mitochondrial membrane potential that accompanies cell death. In this study we show, using a cross-linking approach, that M11L physically associates with the mitochondrial peripheral benzodiazepine receptor (PBR) component of the permeability transition (PT) pore. Close association of M11L and the PBR is also indicated by fluorescence resonance energy transfer (FRET) analysis. Stable expression of M11L prevents the release of mitochondrial cytochrome c induced by staurosporine or protoporphyrin IX (PPIX), a ligand of the PBR. Transiently expressed M11L also prevents mitochondrial membrane potential loss induced by PPIX, or induced by staurosporine in combination with PK11195, another ligand of the PBR. Myxoma virus infection and the associated expression of early proteins, including M11L, protects cells from staurosporine- and Fas-mediated mitochondrial membrane potential loss and this effect is augmented by the presence of PBR. We conclude that M11L regulates the mitochondrial permeability transition pore complex, most likely by direct modulation of the PBR.
Everett
Helen
H
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G2H7, Canada.
Barry
Michele
M
Sun
Xuejun
X
Lee
Siow Fong
SF
Frantz
Christine
C
Berthiaume
Luc G
LG
McFadden
Grant
G
Bleackley
R Chris
RC
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D019169:Jurkat Cells; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009233:Myxoma virus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2; D011524:Protoporphyrins; D011963:Receptors, GABA-A; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C077309:M11L protein, Myxoma virus; C028025:protoporphyrin IX