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J. Biol. Chem., Vol. 281, Issue 51, 39728-39739, December 22, 2006

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The Vaccinia Virus Protein F1L Interacts with Bim and Inhibits Activation of the Pro-apoptotic Protein Bax^*

From the Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Vaccinia virus, the prototypic member of the orthopoxvirus genus, encodes the mitochondrial-localized protein F1L that functions to protect cells from apoptotic death and inhibits cytochrome c release. We previously showed that F1L interacts with the pro-apoptotic Bcl-2 family member Bak and inhibits activation of Bak following an apoptotic stimulus (Wasilenko, S. T., Banadyga, L., Bond, D., and Barry, M. (2005) J. Virol. 79, 14031-14043). In addition to Bak, the pro-apoptotic protein Bax is also capable of initiating cytochrome c release suggesting that vaccinia virus infection could also inhibit Bax activity. Here we show that F1L inhibits the activity of the pro-apoptotic protein Bax by inhibiting oligomerization and N-terminal activation of Bax. F1L expression also inhibited the subcellular redistribution of Bax to the mitochondria and the insertion of Bax into the outer mitochondrial membrane. The ability of F1L to inhibit Bax activation does not require Bak, because F1L expression inhibited cytochrome c release and Bax activation in Bak-deficient cells. No interaction between Bax and F1L was detected during infection, suggesting that F1L functions upstream of Bax activation. Notably, F1L was capable of interacting with the BH3-only protein BimL as shown by co-immunoprecipitation, and F1L expression inhibited apoptosis induced by BimL. These studies suggest that, in addition to interacting with the pro-apoptotic protein Bak, F1L also functions to indirectly inhibit the activation of Bax, likely by interfering with the pro-apoptotic activity of BH3-only proteins such as BimL.

Received for publication, August 7, 2006 , and in revised form, October 16, 2006.

^* This work was supported in part by grants from the Canadian Institutes for Medical Research (CIHR) and the Howard Hughes Medical Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by stipends from the Alberta Heritage Foundation for Medical Research and the Natural Sciences and Engineering Research Council of Canada (NSERC).

² Supported by a stipend from NSERC.

³ A Senior Scholar of the Alberta Heritage Foundation for Medical Research, a CIHR New Investigator, and a Howard Hughes International Scholar in Infection and Parasitology. To whom correspondence should be addressed: Dept. of Medical Microbiology and Immunology, 621 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-0702; Fax: 780-492-9828; E-mail: michele.barry{at}ualberta.ca.

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