title: Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, NY 11794, USA.
authors.forename: Tsu-Fan
authors.initials: TF
authors.lastname: Cheng
authors.forename: Sabrina
authors.initials: S
authors.lastname: Brzostek
authors.forename: Osamu
authors.initials: O
authors.lastname: Ando
authors.forename: Sarah
authors.initials: S
authors.lastname: Van Scoy
authors.forename: K Prasanna
authors.initials: KP
authors.lastname: Kumar
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Reich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D050881:E1A-Associated p300 Protein; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009522:Newcastle disease virus / Q000276:immunology*; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C494232:IRF3 protein, human; C431713:IRF5 protein, human; D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; C494233:Irf3 protein, mouse; D009687:Nuclear Proteins; D007371:Interferon-gamma; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D050880:p300-CBP Transcription Factors