Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1.
Recognition of double-stranded RNA activates interferon-regulatory factor 3 (IRF3)-dependent expression of antiviral factors. Although the molecular mechanisms underlying the activation of IRF3 have been studied, the mechanisms by which IRF3 activity is reduced have not. Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339-Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. These results elucidate a previously unknown mechanism for controlling innate antiviral responses by negatively regulating IRF3 activity via Pin1.
Saitoh
Tatsuya
T
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Tun-Kyi
Adrian
A
Ryo
Akihide
A
Yamamoto
Masahiro
M
Finn
Greg
G
Fujita
Takashi
T
Akira
Shizuo
S
Yamamoto
Naoki
N
Lu
Kun Ping
KP
Yamaoka
Shoji
S
D000818:Animals; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D015536:Down-Regulation; D007113:Immunity, Innate / Q000235:genetics*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011392:Proline / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020365:RNA Helicases / Q000378:metabolism; D034622:RNA Interference; D012327:RNA Virus Infections / Q000235:genetics / Q000276:immunology*; D012328:RNA Viruses / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000378:metabolism / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism
D050838:Interferon Regulatory Factor-3; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012330:RNA, Double-Stranded; D051196:Toll-Like Receptor 3; D025801:Ubiquitin; D012694:Serine; D016899:Interferon-beta; D011392:Proline; D046988:Proteasome Endopeptidase Complex; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse