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Journal of Virology, November 2001, p. 10409-10420, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10409-10420.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Poliovirus Protein 3A Inhibits Tumor Necrosis Factor (TNF)-Induced Apoptosis by Eliminating the TNF Receptor from the Cell Surface

Nickolay Neznanov,1,2,* Anna Kondratova,1,3,dagger Konstantin M. Chumakov,4 Brigitte Angres,5 Bakhyt Zhumabayeva,5 Vadim I. Agol,6,7 and Andrei V. Gudkov1,*

Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 606071; Quark Biotech, Inc., Pleasanton, California 945662; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 117984,3 M. P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, Moscow Region 142782,6 and Moscow State University, Moscow 119899,7 Russia; Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 208524; and Clontech Laboratories, Palo Alto, California 943035

Received 26 March 2001/Accepted 16 July 2001

Viral infections often trigger host defensive reactions by activating intrinsic (intracellular) and extrinsic (receptor-mediated) apoptotic pathways. Poliovirus is known to encode an antiapoptotic function(s) suppressing the intrinsic pathway. Here, the effect of poliovirus nonstructural proteins on cell sensitivity to tumor necrosis factor (TNF)-induced (i.e., receptor-mediated) apoptosis was studied. This sensitivity is dramatically enhanced by the viral proteinase 2A, due, most likely, to inhibition of cellular translation. On the other hand, cells expressing poliovirus noncapsid proteins 3A and 2B exhibit strong TNF resistance. Expression of 3A neutralizes the proapoptotic activity of 2A and results in a specific suppression of TNF signaling, including the lack of activation of NF-kappa B, due to elimination of the TNF receptor from the cell surface. In agreement with this, poliovirus infection results in a dramatic decrease in TNF receptor abundance on the surfaces of infected cells as early as 4 h postinfection. Poliovirus proteins that confer resistance to TNF interfere with endoplasmic reticulum-Golgi protein trafficking, and their effect on TNF signaling can be imitated by brefeldin A, suggesting that the mechanism of poliovirus-mediated resistance to TNF is a result of aberrant TNF receptor trafficking.

* Corresponding author. Present address: Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195. Phone: (216) 445-1205. Fax: (216) 444-0512. E-mail for Nickolay Neznanov: neznann{at}ccf.org. E-mail for Andrei V. Gudkov: gudkov{at}ccf.org.

dagger Present address: Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.

Journal of Virology, November 2001, p. 10409-10420, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10409-10420.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.