Interferon-gamma mRNA attenuates its own translation by activating PKR: a molecular basis for the therapeutic effect of interferon-beta in multiple sclerosis.
PKR, the interferon (IFN)-inducible protein kinase activated by double-stranded RNA, inhibits translation by phosphorylating the initiation factor eIF2alpha chain. Uniquely, human IFN-gamma mRNA uses local activation of PKR in the cell to control its own translation yield. IFN-gamma 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-gamma mRNA to activate PKR and strongly increase its translation efficiency. The cis-acting RNA element in IFN-gamma mRNA functions as a biological sensor of intracellular PKR levels. During an immune response, as IFN-gamma 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-gamma mRNA. With the resulting phosphorylation of eIF2alpha, a negative feedback loop is created and the production of IFN-gamma is progressively attenuated. We propose that the therapeutic effect of IFN-beta 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-gamma mRNA translation through this negative feedback loop, blocking the excessive IFN-gamma gene expression that precedes clinical attacks.
Department of Molecular Virology, The Hebrew University-Hadassah Medical School, 91120 Jerusalem, Israel. kaempfer@hebrew.edu
Raymond
R
Kaempfer
D020121:5' Untranslated Regions; D001483:Base Sequence; D004789:Enzyme Activation; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism / Q000627:therapeutic use; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
D020121:5' Untranslated Regions; D012333:RNA, Messenger; D016899:Interferon-beta; D007371:Interferon-gamma; D019892:eIF-2 Kinase