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Journal of Virology, June 2002, p. 5701-5710, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5701-5710.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Langat Flavivirus Protease NS3 Binds Caspase-8 and Induces Apoptosis

Grigori G. Prikhod'ko,1* Elena A. Prikhod'ko,2 Alexander G. Pletnev,1 and Jeffrey I. Cohen2

Laboratory of Infectious Diseases,1 Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208922

Received 18 October 2001/ Accepted 1 March 2002

The flavivirus NS3 protein plays an important role in the cleavage and processing of the viral polyprotein and in the synthesis of the viral RNA. NS3 recruits NS2B and NS5 proteins to form complexes possessing protease and replicase activities through protease and nucleoside triphosphatase/helicase domains. We have found that NS3 also induces apoptosis. Expression of the Langat (LGT) virus NS3 protein resulted in a cleavage of cellular DNA and reduced the viability of cells. Coexpression of NS3 with apoptotic inhibitors (CrmA and P35) and addition of caspase peptide substrates (Z-VAD-FMK and Z-IETD-FMK) to NS3-transfected cells blocked NS3-induced apoptosis. In cotransfection experiments, NS3 bound to caspase-8 and enhanced caspase-8-mediated apoptosis. NS3 and caspase-8 colocalized in the cytoplasm of transfected cells. Deletion analysis demonstrated that at least two regions of NS3 contribute to its apoptotic activities. The protease and helicase domains are each able to bind to caspase-8, while the protease domain alone induces apoptosis. The protease domain and tetrahelix region of the helicase domain are required for NS3 to augment caspase-8-mediated apoptosis. Thus, the LGT virus NS3 protein is a multifunctional protein that binds to caspase-8 and induces apoptosis.

* Corresponding author. Mailing address: Plasma Derivatives Department, American Red Cross Holland Laboratory, 15601 Crabbs Branch Way, Rockville, MD 20855-2743 Phone: (301) 738-0756. Fax: (301) 738-0708. E-mail: PrikhodkoG{at}usa.redcross.org.

Journal of Virology, June 2002, p. 5701-5710, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5701-5710.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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