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. / Virology
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1761 |
| Date | 06 1900 |
| Creators | Banadyga, Logan Elliott |
| Contributors | Barry, Michele (Medical Microbiology and Immunology), Baksh, Shairaz (Pediatrics), Smiley, James (Medical Microbiology and Immunology), Goping, Ing Swie (Biochemistry), Shisler, Joanna (Medical Microbiology, University of Illinois at Urbana-Champaign) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 28165063 bytes, application/pdf |
| Relation | Banadyga L., Gerig J., Stewart T., and M. Barry. 2007. Journal of Virology. 81(20):11032-45. Copyright 2007. American Society for Microbiology., Banadyga L., Veugelers K., Campbell S., and M. Barry. 2009. Journal of Virology. 83(14):7085-98. Copyright 2009. American Society for Microbiology., Banadyga L., Lam S-C., Okamoto T., Kvansakul M., Huang D.C., and M. Barry. 2011. Journal of Virology. 85(5). Copyright 2011. American Society for Microbiology. |
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