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: Irina Krasnoselskaya-Riz, Aliyah Spruill, Yi-Wen Chen, David Schuster, Theresa Teslovich, Carl Baker, Ajit Kumar, Dietrich A Stephan
• Journal: AIDS research and human retroviruses (AIDS Res Hum Retroviruses) Vol. 18 Issue 8 Pg. 591-604 (May 20 2002) ISSN: 0889-2229 [Print] United States
• PMID: 12036489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Primers
• DNA-Binding Proteins
• NFATC Transcription Factors
• Nuclear Factor 90 Proteins
• Nuclear Proteins
• RNA, Messenger
• Transcription Factors
• Interferons

Topics

• Amino Acid Sequence
• Base Sequence
• DNA Primers
• DNA-Binding Proteins (chemistry, genetics, physiology)
• Gene Expression Regulation (physiology)
• HIV Infections (immunology)
• Humans
• Immunity, Cellular
• Interferons (genetics)
• Molecular Sequence Data
• NFATC Transcription Factors
• Nuclear Factor 90 Proteins
• Nuclear Proteins
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sequence Homology, Amino Acid
• Transcription Factors (chemistry, genetics, physiology)
• Tumor Cells, Cultured