¹Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel

Correspondence: Raymond Kaempfer, Tel: +972-2-675-8389, Fax: +972-2-678-4010; E-mail: kaempfer@hebrew.edu

Abstract

PKR, the interferon (IFN)-inducible protein kinase activated by double-stranded RNA, inhibits translation by phosphorylating the initiation factor eIF2 chain. Uniquely, human IFN- mRNA uses local activation of PKR in the cell to control its own translation yield. IFN- 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- mRNA to activate PKR and strongly increase its translation efficiency. The cis-acting RNA element in IFN- mRNA functions as a biological sensor of intracellular PKR levels. During an immune response, as IFN- 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- mRNA. With the resulting phosphorylation of eIF2, a negative feedback loop is created and the production of IFN- is progressively attenuated. We propose that the therapeutic effect of IFN- 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- mRNA translation through this negative feedback loop, blocking the excessive IFN- gene expression that precedes clinical attacks.