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

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Affiliations

  • 1. Department of Molecular Biology, Princeton University, 216 Schultz Laboratory, Princeton, NJ 08540, USA.
      Authors
    • Han Y 1
    (1 author)

Cell Reports, 19 Oct 2012, 2(4):902-913
https://doi.org/10.1016/j.celrep.2012.09.004 PMID: 23084743 

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.

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Read article at publisher's site: https://doi.org/10.1016/j.celrep.2012.09.004

Read article for free, from open access legal sources, via Unpaywall: https://www.cell.com/article/S2211124712002859/pdfUnpaywall

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