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Journal of Virology, July 2005, p. 8004-8013, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8004-8013.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of Alpha/Beta Interferon Signaling by the NS4B Protein of Flaviviruses

Jorge L. Muñoz-Jordán,1,{dagger} Maudry Laurent-Rolle,1 Joseph Ashour,1,2 Luis Martínez-Sobrido,1 Mundrigi Ashok,3 W. Ian Lipkin,3 and Adolfo García-Sastre1*

Department of Microbiology,1 Microbiology Graduate School Training Program, Mount Sinai School of Medicine, New York, New York 10029,2 Jerome L. and Dawn Greene Infectious Disease Laboratory, Mailman School of Public Health, Columbia University, New York, New York 100323

Received 11 November 2004/ Accepted 5 March 2005

Flaviviruses are insect-borne, positive-strand RNA viruses that have been disseminated worldwide. Their genome is translated into a polyprotein, which is subsequently cleaved by a combination of viral and host proteases to produce three structural proteins and seven nonstructural proteins. The nonstructural protein NS4B of dengue 2 virus partially blocks activation of STAT1 and interferon-stimulated response element (ISRE) promoters in cells stimulated with interferon (IFN). We have found that this function of NS4B is conserved in West Nile and yellow fever viruses. Deletion analysis shows that that the first 125 amino acids of dengue virus NS4B are sufficient for inhibition of alpha/beta IFN (IFN-{alpha}/ß) signaling. The cleavable signal peptide at the N terminus of NS4B, a peptide with a molecular weight of 2,000, is required for IFN antagonism but can be replaced by an unrelated signal peptide. Coexpression of dengue virus NS4A and NS4B together results in enhanced inhibition of ISRE promoter activation in response to IFN-{alpha}/ß. In contrast, expression of the precursor NS4A/B fusion protein does not cause an inhibition of IFN signaling unless this product is cleaved by the viral peptidase NS2B/NS3, indicating that proper viral polyprotein processing is required for anti-interferon function.

* Corresponding author. Mailing address: Department of Microbiology, Box 1124. Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029. Phone: (212) 241-7769. Fax: (212) 534-1684. E-mail: adolfo.garcia-sastre{at}mssm.edu.

{dagger} Present address: Centers for Disease Control and Prevention, Division of Vector-Born Infectious Diseases, Dengue Branch, 1324 Calle Cañada, San Juan, Puerto Rico 00920-3860.

Journal of Virology, July 2005, p. 8004-8013, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8004-8013.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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