Interferon regulatory factor-3 is an in vivo target of DNA-PK.
Eukaryotic cells have evolved complex signaling networks to sense environmental stress and to repair stress-induced damage. IFN regulatory factor-3 (IRF-3) is a transcription factor that plays a central role in the host response to viral infection. Although the main activity of IRF-3 characterized to date has been its role in the induction of IFN-alpha and -beta after virus infection, recent evidence indicates additional roles for IRF-3 in the response to DNA damage and in virus-induced apoptosis. Here we identify IRF-3 as the first in vivo target for DNA-dependent protein kinase (DNA-PK). Phosphorylation of IRF-3 by DNA-PK after virus infection results in its nuclear retention and delayed proteolysis. These results expand the known roles of DNA-PK and provide a functional link between the cellular machineries that regulate the innate immune response and that sense and respond to DNA damage. As such this study contributes to a more integrated view of the cellular responses to various cellular stress signals.
Karpova
Alla Y
AY
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Trost
Maren
M
Murray
John M
JM
Cantley
Lewis C
LC
Howley
Peter M
PM
D016475:3T3 Cells; D000818:Animals; D002467:Cell Nucleus / Q000502:physiology; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3; D007700:Kinetics; D051379:Mice; D009687:Nuclear Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011817:Rabbits; D029082:Sendai virus / Q000502:physiology; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D013912:Threonine; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases