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

Author(s): Han, Yuchen; Whitney, Gena; Donovan, Jesse; Korennykh, Alexei

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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.
Publication Date: 19-Oct-2012
Citation: Han, Yuchen, Whitney, Gena, Donovan, Jesse, Korennykh, Alexei. (2012). Innate immune messenger 2-5A tethers human RNase L into active high-order complexes. Cell Reports, 2 (4), 902 - 913. doi:10.1016/j.celrep.2012.09.004
DOI: doi:10.1016/j.celrep.2012.09.004
ISSN: 2211-1247
EISSN: 2211-1247
Pages: 902 - 913
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Cell Reports
Version: Final published version. This is an open access article.

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