Apoptosis

, Volume 16, Issue 3, pp 256–271 | Cite as

The ribonucleotide reductase R1 subunits of herpes simplex virus types 1 and 2 protect cells against TNFα- and FasL-induced apoptosis by interacting with caspase-8

  • Florent Dufour
  • A. Marie-Josée Sasseville
  • Stéphane Chabaud
  • Bernard Massie
  • Richard M. Siegel
  • Yves Langelier
Original Paper

Abstract

We previously reported that HSV-2 R1, the R1 subunit (ICP10; UL39) of herpes simplex virus type-2 ribonucleotide reductase, protects cells against apoptosis induced by the death receptor (DR) ligands tumor necrosis factor-alpha- (TNFα) and Fas ligand (FasL) by interrupting DR-mediated signaling at, or upstream of, caspase-8 activation. Further investigation of the molecular mechanism underlying HSV-2 R1 protection showed that extracellular-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K)/Akt, NF-κB and JNK survival pathways do not play a major role in this antiapoptotic function. Interaction studies revealed that HSV-2 R1 interacted constitutively with caspase-8. The HSV-2 R1 deletion mutant R1(1-834)-GFP and Epstein–Barr virus (EBV) R1, which did not protect against apoptosis induced by DR ligands, did not interact with caspase-8, indicating that interaction is required for protection. HSV-2 R1 impaired caspase-8 activation induced by caspase-8 over-expression, suggesting that interaction between the two proteins prevents caspase-8 dimerization/activation. HSV-2 R1 bound to caspase-8 directly through its prodomain but did not interact with either its caspase domain or Fas-associated death domain protein (FADD). Interaction between HSV-2 R1 and caspase-8 disrupted FADD-caspase-8 binding. We further demonstrated that individually expressed HSV-1 R1 (ICP6) shares, with HSV-2 R1, the ability to bind caspase-8 and to protect cells against DR-induced apoptosis. Finally, as the long-lived Fas protein remained stable during the early period of infection, experiments with the HSV-1 UL39 deletion mutant ICP6∆ showed that HSV-1 R1 could be essential for the protection of HSV-1-infected cells against FasL.

Keywords

FasL ICP6 ICP10 Viral inhibitor of apoptosis Caspase-8 

Notes

Acknowledgments

This work was supported by Canadian Institutes of Health Research Grant NRF #67052. We thank Angela Pearson, Andrew D. Badley, Marcus E. Peter and Joseph S. Pagano for their kind gifts of plasmids and antibodies, Sandra Weller for the generous donation of ICP6∆, Pascal Schneider for its kind gift of Fc:FasL, and W. Edward C. Bradley as well as Richard Bertrand for critical manuscript editing. This is National Research Council of Canada publication No. 52767.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10495_2010_560_MOESM1_ESM.pdf (1.5 mb)
Supplementary material 1 (PDF 1549 kb)

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Florent Dufour
    • 1
  • A. Marie-Josée Sasseville
    • 1
  • Stéphane Chabaud
    • 1
    • 7
  • Bernard Massie
    • 2
    • 3
    • 4
  • Richard M. Siegel
    • 5
  • Yves Langelier
    • 1
    • 2
    • 6
  1. 1.Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM) and Institut du cancer de MontréalHôpital Notre-DameMontrealCanada
  2. 2.Département de microbiologie et immunologieUniversité de MontréalMontrealCanada
  3. 3.Institut de recherche en biotechnologieMontrealCanada
  4. 4.Institut national de la recherche scientifique-Institut Armand-FrappierUniversité du QuébecLavalCanada
  5. 5.Immunoregulation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institutes of HealthBethesdaUSA
  6. 6.Département de médecineUniversité de MontréalMontrealCanada
  7. 7.Laboratoire d’Organogénèse Expérimentale (LOEX)Université LavalQuebecCanada

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