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Journal of Virology, July 2004, p. 7097-7111, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7097-7111.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Myxoma Virus M11L Prevents Apoptosis through Constitutive Interaction with Bak

Gen Wang,1 John W. Barrett,1 Steven H. Nazarian,1 Helen Everett,1,{dagger} Xiujuan Gao,1 Chris Bleackley,2 Karen Colwill,3,{ddagger} Michael F. Moran,3 and Grant McFadden1*

Department of Microbiology and Immunology, University of Western Ontario and Robarts Research Institute, London, Ontario N6G 2V4,1 Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7,2 MDS Proteomics, Toronto, Ontario M9W 7H4, Canada3

Received 4 December 2003/ Accepted 4 March 2004

M11L, a 166-amino-acid antiapoptotic protein of myxoma virus, was previously shown to bind to the peripheral benzodiazepine receptor by hydrophobic interactions at the outer mitochondrial membrane. Here we demonstrate that an additional property of M11L is the ability to constitutively form inhibitory complexes with the proapoptotic Bcl-2 family member Bak in human cells. This binding interaction was identified by both FLAG-tagged pull-down assays and tandem affinity purification from transfected and virus-infected human cells. M11L binds constitutively to human Bak and, under some inducible conditions, to human Bax as well, but not to the other Bcl-2 family members (Bad, Bid, Bcl-2). When stably expressed in human embryonic kidney (HEK293) cells, M11L effectively protects these cells from Fas ligand-induced apoptosis, thereby blocking release of cytochrome c, activation of caspase 9, and cleavage of poly(ADP-ribose) polymerase. We also demonstrate in coexpression studies that M11L can interact with Bak independently of any involvement with Bax. Furthermore, cells stably expressing M11L function to prevent apoptosis that is induced by overexpression of Bak. We conclude that M11L inhibits, in a species-independent fashion, apoptotic signals mediated by activation of Bak.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Western Ontario and Robarts Research Institute, 1400 Western Rd., London, ON N6G 2V4, Canada. Phone: (519) 663-3184. Fax: (519) 663-3847. E-mail: mcfadden{at}robarts.ca.

{dagger} Present address: Institut de Biochimie, Université de Lausanne, Epalinges, Lausanne, CH-1066 Switzerland.

{ddagger} Present address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

Journal of Virology, July 2004, p. 7097-7111, Vol. 78, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.13.7097-7111.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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