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

• DOI: 10.1016/j.celrep.2012.09.004
• Publication Date: 2012-10-19T02:33:07Z
• Authors: Yuchen Han; Gena Whitney; Jesse Donovan; Alexei Korennykh
• Keywords: Ankyrin repeat; RNase MRP; Second messenger system

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 RNase L, which cleaves cytosolic RNA promotes production interferons (IFNs) cytokines driven by transcription factors IRF-3 NF-κB. We report that human L is activated forming high-order complexes, reminiscent mode phylogenetically related transmembrane kinase/RNase Ire1 unfolded protein response. describe crystal structures determined at 2.4 Å 2.8 resolution, show two molecules 2-5A a time tether monomers via ankyrin-repeat (ANK) domain. Each ANK domain harbors distinct sites for recognition reside 50 apart. These data reveal function 2-5A-sensing homo-oligomerization device nonlinear, ultrasensitive regulation 2-5A/RNase system poised amplification IFN