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

• Author / Creator

  Banadyga, Logan Elliott

• 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.

• Subjects / Keywords

  • Fowlpox
  • Bax
  • Bak
  • Apoptosis
  • Immunomodulation
  • Poxvirus
  • Bcl-2

• Graduation date

  Spring 2011

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3KX0F

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.