Interferon-γ mRNA attenuates its own translation by activating PKR： A molecular basis for the therapeutic effect of interferon-β in multiple sclerosis  

作　　者：Raymond Kaempfer 

机构地区：[1]Oepartment of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel

出　　处：《Cell Research》2006年第2期148-153,共6页细胞研究（英文版）

基　　金：Acknowledgements Research in the author＇s laboratory was supported by grants from the Israel Science Foundation （537/03） and the Deutsche Forschungsgemeinschaft （H0- 1116）,

摘　　要：PKR, the interferon （IFN）-inducible protein kinase activated by double-stranded RNA, inhibits translation by phosphorylating the initiation factor eIF2α chain. Uniquely, human IFN-γ mRNA uses local activation of PKR in the cell to control its own translation yield. IFN-γ mRNA activates PKR through a structure in its 5＇- region harboring a pseudoknot which is critical for PKR activation. Mutations that impair pseudoknot stability reduce the ability of IFN-γ mRNA to activate PKR and strongly increase its translation efficiency. The cis-acting RNA element in IFN-γ mRNA functions as a biological sensor of intracellular PKR levels. During an immune response, as IFN-γ and other inflammatory cytokines build up in the cell＇s microenvironment, they act to induce higher levels of PKR in the cell, resulting in a more extensive activation of PKR by IFN-γ mRNA. With the resulting phosphorylation of eIF2α, a negative feedback loop is created and the production of IFN-γ is progressively attenuated. We propose that the therapeutic effect of IFN-β in multiple sclerosis may rest, at least in part, on its exquisite ability to induce high levels of PKR in the cell and thereby to limit IFN-γ mRNA translation through this negative feedback loop, blocking the excessive IFN-γ gene expression that precedes clinical attacks.

关 键 词：INTERFERON-Γ MRNA RNA pseudoknot translational control PKR eIF2 multiple sclerosis INTERFERON-Β 

分 类 号：R593[医药卫生—内科学]