Human interferon-γ mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR

PKR, an interferon (IFN)-inducible protein kinase activated by double-stranded RNA, inhibits translation by phosphorylating the initiation factor eIF2α chain. We show that 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 pseudoknot in its 5′ untranslated region. Mutations that impair pseudoknot stability reduce the ability to activate PKR and strongly increase the translation efficiency of IFN-γ mRNA. Nonphosphorylatable mutant eIF2α, knockout of PKR and PKR inhibitors 2-aminopurine, transdominant-negative PKR, or vaccinia E3L correspondingly enhances translation of IFN-γ mRNA. The potential to form the pseudoknot is phylogenetically conserved. We propose that the RNA pseudoknot acts to adjust translation of IFN-γ mRNA to the PKR level expressed in the cell.