The vaccinia virus protein F1L interacts with Bim and inhibits activation of the pro-apoptotic protein Bax.
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.
Taylor
John M
JM
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Quilty
Douglas
D
Banadyga
Logan
L
Barry
Michele
M
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D014616:Vaccinia virus / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C507356:F1L protein, vaccinia virus; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014764:Viral Proteins; D051028:bcl-2-Associated X Protein