Persistent prion infection disturbs the function of Oct-1, resulting in the down-regulation of murine interferon regulatory factor-3

Homma, Takujiro; Ishibashi, Daisuke; Nakagaki, Takehiro; Fuse, Takayuki; Sano, Kazunori; Satoh, Katsuya; Atarashi, Ryuichiro; Nishida, Noriyuki

Prion diseases are neurodegenerative disorders characterized by an aggregation of abnormal prion protein (PrP Sc ) 8 . Since PrP Sc itself seems to be an infectious agent and the protein is host-encoded, acquired immunity against prion disease should not be possible. Conversely, we previously demonstrated that IRF-3 plays a crucial role in the host's defense mechanism against prion infection. Disrupted IRF-3 genes developed prion diseases earlier compared to wild-type mice after inoculation. Overexpression of IRF-3 significantly reduced the amount of abnormal prion protein in persistently infected cells, indicating that IRF-3 expression levels are closely related to the anti-prion state of the host cell 9, 10 . Although the innate immune responses against prion invasion are insufficient to stop disease progression, involvement of IRF-3 inducible factors such as IFN-I may be one of the reasons why prion infection shows an extremely long incubation period. It would be of great benefit to understand how IRF-3 inducible factors inhibit prion infection and how prions avoid this host-defense system. Lowther et al. reported that a sufficient basal promoter activity of human IRF-3 was found in the upstream region (nucleotides: nt; -113 to -1) of the transcription start site 11 , however, the mechanism of the transcriptional regulation of IRF-3 remains largely unknown. In this study, we analyzed murine IRF-3 promoter activity in detail and its relationship to prion infection, and have shown that the octamer-binding transcription factor-1 (Oct-1) positively regulates murine IRF-3, and the expression levels of Oct-1 decreased in prion-infected cells.