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Permanent link (DOI): https://doi.org/10.7939/R3KX0F

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Poxviral manipulation of Bcl-2 proteins: fowlpox virus FPV039 and deerpox virus DPV022 inhibit apoptosis by neutralising Bak and Bax, while Noxa contributes to vaccinia virus-induced apoptosis Open Access

Descriptions

Other title
Subject/Keyword
Immunomodulation
Bak
Apoptosis
Fowlpox
Bcl-2
Bax
Poxvirus
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Banadyga, Logan Elliott
Supervisor and department
Barry, Michele (Medical Microbiology and Immunology)
Examining committee member and department
Goping, Ing Swie (Biochemistry)
Smiley, James (Medical Microbiology and Immunology)
Shisler, Joanna (Medical Microbiology, University of Illinois at Urbana-Champaign)
Baksh, Shairaz (Pediatrics)
Department
Department of Medical Microbiology and Immunology
Specialization

Date accepted
2011-01-27T16:21:04Z
Graduation date
2011-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Poxviruses are renowned for encoding proteins that modulate virtually every aspect of the host immune system. One effective barrier against virus infection is apoptosis, a form of programmed cell death. Apoptosis is controlled at the mitochondria by pro- and anti-apoptotic members of the highly conserved Bcl-2 family of proteins, and two members in particular, Bak and Bax, are absolutely critical to the induction of cell death. Although poxviruses encode an array of effective inhibitors of apoptosis, only members of the Avipoxvirus genus, of which fowlpox virus is the prototypical member, encode proteins with obvious, albeit limited, sequence identity to cellular Bcl-2 proteins. Fowlpox virus, the prototypical avipoxvirus, encodes FPV039, a protein that possesses two of the four highly conserved Bcl-2 homology (BH) domains that characterise the Bcl-2 family. Here we demonstrate that, like cellular Bcl-2 proteins, FPV039 localised to the mitochondria where it prevented apoptosis induced by a variety of cytotoxic stimuli, including virus infection itself. FPV039 inhibited apoptosis induced by Bak and Bax through an interaction with Bak and activated Bax. FPV039 also interacted with a discrete subset of BH3-only proteins, the upstream activators of Bak and Bax, to prevent Bax activation in the first place. Additionally, we have characterised the function and mechanism of action of a novel deerpox virus protein, DPV022. Intriguingly, DPV022 lacks obvious homology to cellular Bcl-2 proteins but shares limited regions of amino acid identity with two other poxviral inhibitors of apoptosis, vaccinia virus F1L and myxoma virus M11L, which are themselves unrelated. Here we demonstrate that DPV022 localised to the mitochondria where it interacted directly with Bak and Bax to inhibit apoptosis, even in the absence all cellular anti-apoptotic Bcl-2 proteins. We have also embarked on a preliminary analysis of the apical events that initially trigger apoptosis during infection with vaccinia virus, the prototypical poxvirus. Accordingly, we demonstrate that the BH3-only protein Noxa contributed to the vaccinia virus-induced apoptotic response, possibly through an involvement with dsRNA. Together, this study represents a comprehensive analysis of the ways in which poxviruses manipulate the cellular Bcl-2 family of proteins, the arbiters of cell death.
Language
English
DOI
doi:10.7939/R3KX0F
Rights
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.
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