Title | Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Cheng T-F, Brzostek S, Ando O, Van Scoy S, K Kumar P, Reich NC |
Journal | J Immunol |
Volume | 176 |
Issue | 12 |
Pagination | 7462-70 |
Date Published | 2006 Jun 15 |
ISSN | 0022-1767 |
Keywords | Amino Acid Sequence, Animals, Apoptosis, Cell Line, Tumor, CREB-Binding Protein, Dimerization, E1A-Associated p300 Protein, Gene Expression Regulation, HeLa Cells, Humans, Interferon Regulatory Factor-3, Interferon Regulatory Factors, Interferon-gamma, Mice, Mice, Knockout, Molecular Sequence Data, Mutagenesis, Site-Directed, Newcastle disease virus, Nuclear Proteins, p300-CBP Transcription Factors, Protein Binding, Regulatory Sequences, Nucleic Acid |
Abstract | Members of the IFN regulatory factor (IRF) family regulate gene expression critical to immune response, hemopoiesis, and proliferation. Although related by homology at their N-terminal DNA-binding domain, they display individual functional properties. The distinct properties result from differences in regulated expression, response to activating signals, and interaction with DNA regulatory elements. IRF-3 is expressed ubiquitously and is activated by serine phosphorylation in response to viral infection or TLR signaling. Evidence indicates that the kinases TANK-binding kinase 1 and inhibitor of NF-kappaB kinase-epsilon specifically phosphorylate and thereby activate IRF-3. We evaluated the contribution of another member of the IRF family, IRF-5, during viral infection since prior studies provided varied results. Analysis of phosphorylation, nuclear translocation, dimerization, binding to CREB-binding protein, recognition of DNA, and induction of gene expression were used comparatively with IRF-3 as a measure of IRF-5 activation. IRF-5 was not activated by viral infection; however, expression of TANK-binding kinase 1 or inhibitor of NF-kappaB kinase-epsilon did provide clear activation of IRF-5. IRF-5 is therefore distinct in its activation profile from IRF-3. However, similar to the biological effects of IRF-3 activation, a constitutively active mutation of IRF-5 promoted apoptosis. The apoptosis was inhibited by expression of Bcl-x(L) but not a dominant-negative mutation of the Fas-associated death domain. These studies support the distinct activation profiles of IRF-3 in comparison to IRF-5, but reveal a potential shared biological effect. |
DOI | 10.4049/jimmunol.176.12.7462 |
Alternate Journal | J Immunol |
PubMed ID | 16751392 |
Grant List | P01AI0555621 / AI / NIAID NIH HHS / United States P01CA2814 / CA / NCI NIH HHS / United States |
Related Faculty:
Sabrina Racine-Brzostek, M.D., Ph.D.