Triggering the interferon response: the role of IRF-3 transcription factor.
The interferon (IFN) regulatory factors (IRF) consist of a growing family of related transcription proteins first identified as regulators of the IFN-alpha/beta gene promoters, as well as the IFN-stimulated response element (ISRE) of some IFN-stimulated genes. IRF-3 was originally identified as a member of the IRF family based on homology with other IRF family members and on binding to the ISRE of the IFN-stimulated gene 15 (ISG15) promoter. Several recent studies have focused attention on the unique molecular properties of IRF-3 and its role in the regulation of IFN gene expression. IRF-3 is expressed constitutively in a variety of tissues, and the relative levels of IRF-3 mRNA do not change in virus-infected or IFN-treated cells. Following virus infection, IRF-3 is posttranslationally modified by protein phosphorylation at multiple serine and threonine residues, located in the carboxy-terminus of IRF-3. Phosphorylation causes the cytoplasmic to nuclear translocation of IRF-3, stimulation of DNA binding, and increased transcriptional activation, mediated through the association of IRF-3 with the CBP/p300 coactivator. The purpose of this review is to summarize recent investigations demonstrating the important role of IRF-3 in cytokine gene transcription. These studies provide the framework for a model in which virus-dependent phosphorylation of IRF-3 alters protein conformation to permit nuclear translocation, association with transcriptional partners, and primary activation of IFN and IFN-responsive genes.
Lady Davis Institute for Medical Research, Department of Microbiology and Immunology, McGill University, Montreal, Canada. mijh@musica.mcgill.ca
J
J
Hiscott
P
P
Pitha
P
P
Genin
H
H
Nguyen
C
C
Heylbroeck
Y
Y
Mamane
M
M
Algarte
R
R
Lin
D000595:Amino Acid Sequence; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D050838:Interferon Regulatory Factor-3; D007372:Interferons / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation
D016207:Cytokines; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; D014157:Transcription Factors; D007372:Interferons