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Journal of Virology, February 2008, p. 1378-1388, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01941-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Flock House Virus Induces Apoptosis by Depletion of Drosophila Inhibitor-of-Apoptosis Protein DIAP1{triangledown}

Erik W. Settles and Paul D. Friesen*

Institute for Molecular Virology, Department of Biochemistry, and Microbiology Doctoral Training Program, Graduate School and College of Agricultural and Life Sciences, University of Wisconsin—Madison, Madison, Wisconsin 53706

Received 4 September 2007/ Accepted 25 October 2007

The molecular mechanisms by which RNA viruses induce apoptosis and apoptosis-associated pathology are not fully understood. Here we show that flock house virus (FHV), one of the simplest RNA viruses (family, Nodaviridae), induces robust apoptosis of permissive Drosophila Line-1 (DL-1) cells. To define the pathway by which FHV triggers apoptosis in this model invertebrate system, we investigated the potential role of Drosophila apoptotic effectors during infection. Suggesting the involvement of host caspases, the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluromethylketone (z-VAD-fmk) prevented FHV-induced cytopathology and prolonged cell survival. RNA interference-mediated ablation of the principal Drosophila effector caspase DrICE or its upstream initiator caspase DRONC prevented FHV-induced apoptosis and demonstrated direct participation of this intrinsic caspase pathway. Prior to the FHV-induced activation of DrICE, the intracellular level of inhibitor-of-apoptosis (IAP) protein DIAP1, the principal caspase regulator in Drosophila melanogaster, was dramatically reduced. DIAP1 was depleted despite z-VAD-fmk-mediated caspase inhibition during infection, suggesting that the loss of DIAP1 was caused by an upstream FHV-induced signal. The RNA interference-mediated knockdown of DIAP1 caused rapid and uniform apoptosis of DL-1 cells and thus indicated that DIAP1 depletion is sufficient to trigger apoptosis. Confirming this conclusion, the elevation of intracellular DIAP1 levels in stable diap1-transfected cells blocked caspase activation and prevented FHV-induced apoptosis. Collectively, our findings suggest that DIAP1 is a critical sensor of virus infection, which upon virus-signaled depletion relieves caspase inhibition, which subsequently executes apoptotic death. Thus, our study supports the hypothesis that altering the level or the activity of cellular IAP proteins is a general mechanism by which RNA viruses trigger apoptosis.

* Corresponding author. Mailing address: Institute for Molecular Virology, R. M. Bock Laboratories, University of Wisconsin—Madison, 1525 Linden Dr., Madison, WI 53706-1596. Phone: (608) 262-7774. Fax: (608) 262-7414. E-mail: pfriesen{at}wisc.edu

{triangledown} Published ahead of print on 7 November 2007.

Journal of Virology, February 2008, p. 1378-1388, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01941-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Schultz, K. L. W., Friesen, P. D. (2009). Baculovirus DNA Replication-Specific Expression Factors Trigger Apoptosis and Shutoff of Host Protein Synthesis during Infection. J. Virol. 83: 11123-11132 [Abstract] [Full Text]  
  • Stapleford, K. A., Rapaport, D., Miller, D. J. (2009). Mitochondrion-Enriched Anionic Phospholipids Facilitate Flock House Virus RNA Polymerase Membrane Association. J. Virol. 83: 4498-4507 [Abstract] [Full Text]  
  • Schultz, K. L. W., Wetter, J. A., Fiore, D. C., Friesen, P. D. (2009). Transactivator IE1 Is Required for Baculovirus Early Replication Events That Trigger Apoptosis in Permissive and Nonpermissive Cells. J. Virol. 83: 262-272 [Abstract] [Full Text]  


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