Download the full-sized PDF of Investigation of the Anti-apoptotic Function and Regulation of Vaccinia Virus F1LDownload the full-sized PDF



Permanent link (DOI):


Export to: EndNote  |  Zotero  |  Mendeley


This file is in the following communities:

Graduate Studies and Research, Faculty of


This file is in the following collections:

Theses and Dissertations

Investigation of the Anti-apoptotic Function and Regulation of Vaccinia Virus F1L Open Access


Other title
Type of item
Degree grantor
University of Alberta
Author or creator
Campbell, Stephanie D
Supervisor and department
Barry, Michele (Medical Microbiology and Immunology)
Examining committee member and department
Fruh, Klaus (Vaccine and Gene Therapy Institute)
Berthiaume, Luc (Cell Biology)
Barry, Michele (Medical Microbiology and Immunology)
Ingham, Rob (Medical Microbiology and Immunology)
Evans, David (Medical Microbiology and Immunology)
Department of Medical Microbiology and Immunology
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Apoptosis, an evolutionarily conserved cell death programme, is a potent barrier against virus infection. Central to this process are mitochondria, which harbour cytochrome c and other apoptosis-inducing factors. Once released, these factors activate a caspase cascade that culminates in cell death. Mitochondrial integrity is tightly regulated by the Bcl-2 family of proteins, which are united by the presence of one or more conserved Bcl-2 homology, or BH, domains that are critical for protein interactions and function. Bak and Bax are the key pro-apoptotic members that engage the mitochondrial death machinery to release cytochrome c. These proteins are activated by pro-apoptotic BH3-only proteins and inhibited by anti-apoptotic family members, such as Mcl-1. Due to the importance of Bak and Bax, many viruses, including poxviruses, have adapted strategies to interfere with the activation of these two proteins. In the prototypic poxvirus vaccinia virus, this is accomplished by a unique anti-apoptotic protein, F1L. F1L localizes to mitochondria and prevents apoptosis induced by a variety of stimuli. This is achieved by direct binding to Bak, while Bax inhibition is believed to occur by the binding of F1L to the BH3-only protein, BimL. However, the way in which F1L binds Bak and BimL is unknown, since F1L lacks sequence homology to Bcl-2 proteins. Here, we show that F1L functions in a manner that resembles Mcl-1, the major cellular regulator of Bak. Moreover, we have identified divergent BH domains within F1L that are critical for Bak binding and anti-apoptotic activity. Given the importance of the Bcl-2 family of proteins, many members are regulated by ubiquitination, which targets the proteins for proteasomal degradation. Similarly, we have discovered that F1L is tightly regulated by the ubiquitin-proteasome system. Our studies on F1L ubiquitination have also revealed a potential role for F1L in the regulation of mitochondrial morphology. Thus, despite divergence at the sequence level, F1L interacts with Bak in a manner nearly identical to cellular Bcl-2 family members, and, additionally, F1L is governed by the same regulatory mechanisms that control members of the Bcl-2 family.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Campbell, S., B. Hazes, M. Kvansakul, P. Colman, and M. Barry. 2010. Vaccinia virus F1L interacts with Bak using highly divergent Bcl-2 homology domains and replaces the function of Mcl-1. Journal of Biological Chemistry 285:4695-4708.

File Details

Date Uploaded
Date Modified
Audit Status
Audits have not yet been run on this file.
File format: pdf (Portable Document Format)
Mime type: application/pdf
File size: 41382230
Last modified: 2015:10:12 20:51:16-06:00
Filename: uuid_0e1d88c4-1fc4-4b56-ace4-d26a2d69dfdb+DS1+DS1.pdf
Original checksum: 786331373985bd00a7a40df746261a2b
Well formed: true
Valid: false
Status message: Invalid page tree node offset=312458
File title: Blank Page
File title: Life is pleasant
File author: Owner
Activity of users you follow
User Activity Date