Dynamic refolding of IFN-γ mRNA enables it to function as PKR activator and translation template

Smadar Cohen-Chalamish, Anat Hasson, Dahlia Weinberg, Lise Sarah Namer, Yona Banai, Farhat Osman, Raymond Kaempfer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Interferon-γ mRNA activates the RNA-dependent protein kinase PKR, which in turn strongly attenuates translation of interferon-γ mRNA. Unlike riboswitches restricted to noncoding regions, the interferon-γ RNA domain that activates PKR comprises the 5′ UTR and 26 translated codons. Extensive interferon-γ coding sequence is thus dedicated to activating PKR and blocking interferon-γ synthesis. This implies that the PKR activator is disrupted by ribosomes during translation initiation and must refold promptly to restore PKR activation. The activator structure harbors an essential kink-turn, probably to allow formation of a pseudoknot that is critical for PKR activation. Three indispensable short helices, bordered by orientation-sensitive base pairs, align with the pseudoknot stem, generating RNA helix of sufficient length to activate PKR. Through gain-of-function mutations, we show that the RNA activator can adopt alternative conformations that activate PKR. This flexibility promotes efficient refolding of interferon-γ mRNA, which is necessary for its dual function as translation template and activator of PKR, and which thus prevents overexpression of this inflammatory cytokine.

Original languageEnglish
Pages (from-to)896-903
Number of pages8
JournalNature Chemical Biology
Volume5
Issue number12
DOIs
StatePublished - Dec 2009

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