Apoptosis

, 14:1317 | Cite as

The orf virus inhibitor of apoptosis functions in a Bcl-2-like manner, binding and neutralizing a set of BH3-only proteins and active Bax

  • Dana Westphal
  • Elizabeth C. Ledgerwood
  • Joel D. A. Tyndall
  • Merilyn H. Hibma
  • Norihito Ueda
  • Stephen B. Fleming
  • Andrew A. Mercer
Original Paper

Abstract

We have previously shown that the Orf virus protein, ORFV125, is a potent inhibitor of the mitochondrial pathway of apoptosis and displays rudimentary sequence similarities to cellular anti-apoptotic Bcl-2 proteins. Here we investigate the proposal that ORFV125 acts in a Bcl-2-like manner to inhibit apoptosis. We show that the viral protein interacted with a range of BH3-only proteins (Bik, Puma, DP5, Noxa and all 3 isoforms of Bim) and neutralized their pro-apoptotic activity. In addition, ORFV125 bound to the active, but not the inactive, form of Bax, and reduced the formation of Bax dimers. Mutation of specific amino acids in ORFV125 that are conserved and functionally important in mammalian Bcl-2 family proteins led to loss of both binding and inhibitory functions. We conclude that ORFV125’s mechanism of action is Bcl-2-like and propose that the viral protein’s combined ability to bind to a range of BH3-only proteins as well as the active form of Bax provides significant protection against apoptosis. Furthermore, we demonstrate that the binding profile of ORFV125 is distinct to that of other poxviral Bcl-2-like proteins.

Keywords

Apoptosis Mitochondria Bcl-2 family Viral Bcl-2 homolog Poxvirus Orf virus 

Abbreviations

Bcl-2

B-cell leukemia/lymphoma 2

BH

Bcl-2 homology

ORFV

Orf virus

Supplementary material

10495_2009_403_MOESM1_ESM.pdf (575 kb)
Supplementary material 1 (PDF 574 kb)

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Dana Westphal
    • 1
  • Elizabeth C. Ledgerwood
    • 2
  • Joel D. A. Tyndall
    • 3
  • Merilyn H. Hibma
    • 1
  • Norihito Ueda
    • 1
  • Stephen B. Fleming
    • 1
  • Andrew A. Mercer
    • 1
  1. 1.Virus Research Unit, Department of Microbiology and ImmunologyUniversity of OtagoDunedinNew Zealand
  2. 2.Department of BiochemistryUniversity of OtagoDunedinNew Zealand
  3. 3.The National School of PharmacyUniversity of OtagoDunedinNew Zealand

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