4G8L

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

(2012) Cell Rep 2: 902-913

• PubMed: 23084743 Search on PubMed
• DOI: https://doi.org/10.1016/j.celrep.2012.09.004
• Primary Citation of Related Structures:  
  4G8K, 4G8L


• PubMed 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?? and 2.8?? 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?? 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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Organizational Affiliation: 

Department of Molecular Biology, Princeton University, 216 Schultz Laboratory, Princeton, NJ 08540, USA.