Negative regulation of interferon-regulatory factor 3–dependent innate antiviral response by the prolyl isomerase Pin1

Tatsuya Saitoh¹, Adrian Tun-Kyi^2, 8, Akihide Ryo^3, 8, Masahiro Yamamoto⁴, Greg Finn², Takashi Fujita⁵, Shizuo Akira^4, 6, Naoki Yamamoto^1, 7, Kun Ping Lu² & Shoji Yamaoka¹

¹  Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

²  Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

³  Department of Pathology, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan.

⁴  Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.

⁵  Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.

⁶  ERATO, Japan Science and Technology Agency, Osaka 565-0871, Japan.

⁷  AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.

⁸  These authors contributed equally to this work.

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-, 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.

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