Innate Immune Messenger 2-5A Tethers Human RNase L into Active High-Order Complexes

Yuchen Han, Gena Whitney, Jesse Donovan, Alexei V. Korennykh

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)902-913
Number of pages12
JournalCell Reports
Volume2
Issue number4
DOIs
StatePublished - Oct 25 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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