title: Nuclear factor 90 mediates activation of the cellular antiviral expression cascade.
abstract: Viral infection triggers a cascade of interferon response genes, but the mechanisms that prime such innate antiviral defenses are poorly understood. Among candidate cellular mediators of the antiviral response are the double-stranded RNA (dsRNA)-binding proteins. Here we show that a C-terminal variant of the ubiquitous dsRNA-binding protein, nuclear factor 90 (NF90ctv), can activate the interferon response genes in the absence of viral infection. NF90ctv-expressing cells were infected with the syncytium-inducing HIV-1 strain NL4-3 and were shown to inhibit viral replication. To gain insight into this mechanism of protection, we analyzed the expression profiles of NF90ctv-positive cells as compared with parental cells transduced with the empty vector. Of the 5600 genes represented on the expression arrays, 90 displayed significant (4-fold or more) changes in mRNA levels in NF90-expressing cells. About 50% are known interferon alpha/beta-stimulated genes. The microarray expression data were confirmed by quantitative reverse transcriptase-polymerase chain reaction analysis of six representative interferon-inducible genes. Electrophoretic mobility shift assays showed that the biological response is mediated by the activation of transcription factors in NF90ctv-expressing cells. Functional significance of the activated transcription complex was evaluated by transfection assays with luciferase reporter constructs driven by the interferon-inducible promoter from the 2'-5'-oligoadenylate synthetase (p69) gene. Resistance to HIV-1, caused by the expression of NF90ctv in the cell culture system, appears to be mediated in part by the induction of interferon response genes. This leads to a hypothesis as to the mechanism of action of NF90 in mediating endogenous antiviral responses.
authors.affiliation: Department of Biochemistry and Molecular Biology, George Washington University School of Medicine, Washington, D.C. 20037, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Krasnoselskaya-Riz
authors.forename: Aliyah
authors.initials: A
authors.lastname: Spruill
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Schuster
authors.forename: Theresa
authors.initials: T
authors.lastname: Teslovich
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Ajit
authors.initials: A
authors.lastname: Kumar
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007372:Interferons / Q000235:genetics*; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D050779:Nuclear Factor 90 Proteins; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D050779:Nuclear Factor 90 Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D007372:Interferons