Innate immune messenger 2-5A tethers human RNase L into active high-order complexes.
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.
Department of Molecular Biology, Princeton University, 216 Schultz Laboratory, Princeton, NJ 08540, USA.
Yuchen
Y
Han
Gena
G
Whitney
Jesse
J
Donovan
Alexei
A
Korennykh
D000595:Amino Acid Sequence; D017487:Ankyrins / Q000737:chemistry / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray; D019281:Dimerization; D004722:Endoribonucleases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction
D017487:Ankyrins; D003432:Cross-Linking Reagents; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease