Innate immune messenger 2-5A tethers human RNase L into active high-order complexes.

TitleInnate immune messenger 2-5A tethers human RNase L into active high-order complexes.
Publication TypeJournal Article
Year of Publication2012
AuthorsHan, Y, Whitney, G, Donovan, J, Korennykh, A
JournalCell Rep
Date Published2012 Oct 25
KeywordsAmino Acid Sequence, Ankyrins, Cross-Linking Reagents, Crystallography, X-Ray, Dimerization, Endoribonucleases, Humans, Immunity, Innate, Molecular Sequence Data, Oxidation-Reduction, Protein Binding, Protein Multimerization, Protein Structure, Tertiary, Sequence Alignment, Signal Transduction

<p>2',5'-linked oligoadenylates (2-5As) serve as conserved messengers of pathogen presence in the mammalian innate immune system. 2-5As induce self-association and activation of RNase L, which cleaves cytosolic RNA and promotes the production of interferons (IFNs) and cytokines driven by the transcription factors IRF-3 and NF-κB. We report that human RNase L is activated by forming high-order complexes, reminiscent of the mode of activation of the phylogenetically related transmembrane kinase/RNase Ire1 in the unfolded protein response. We describe crystal structures determined at 2.4 Å and 2.8 Å resolution, which show that two molecules of 2-5A at a time tether RNase L monomers via the ankyrin-repeat (ANK) domain. Each ANK domain harbors two distinct sites for 2-5A recognition that reside 50 Å apart. These data reveal a function for the ANK domain as a 2-5A-sensing homo-oligomerization device and describe a nonlinear, ultrasensitive regulation in the 2-5A/RNase L system poised for amplification of the IFN response.</p>

Alternate JournalCell Rep
PubMed ID23084743