title: Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses.
abstract: 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/beta) 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/beta. 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.
authors.affiliation: Department of Microbiology, Box 1124. Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, New York 10029, USA.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Muñoz-Jordán
authors.forename: Maudry
authors.initials: M
authors.lastname: Laurent-Rolle
authors.forename: Joseph
authors.initials: J
authors.lastname: Ashour
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Sobrido
authors.forename: Mundrigi
authors.initials: M
authors.lastname: Ashok
authors.forename: W Ian
authors.initials: WI
authors.lastname: Lipkin
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D005416:Flavivirus / Q000502:physiology*; D016898:Interferon-alpha / Q000187:drug effects / Q000502:physiology*; D016899:Interferon-beta / Q000187:drug effects / Q000502:physiology*; D008322:Mammals; D016133:Polymerase Chain Reaction; D021382:Protein Sorting Signals / Q000187:drug effects / Q000502:physiology*; D015183:Restriction Mapping; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000494:pharmacology*; D014902:West Nile virus / Q000502:physiology*
chemical_list: D017931:DNA Primers; D016898:Interferon-alpha; C080107:NS4B protein, flavivirus; D021382:Protein Sorting Signals; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta