ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation

De Reuver et al. (BioRxiv) DOI: 10.1101/2020.12.04.411702

 

Keywords

  • Sensing

  • Interferon

  • Non-canonical nucleic acids

 

Main Findings

​ADAR1 (Adenosine Deaminase Acting on ds-RNA 1) masks endogenous dsRNA by editing Adenosine-to-Ionosine (A-to-I) to avoid cytosolic sensing by MDA5 (Melanoma differentiation-associated protein 5). ADAR1 edits dsRNA in its canonical form, but also as Z-RNA, a left-handed conformer derived from SINEs (Short Interspersed Nuclear Elements). De Reuver et al. mutate ADAR1 Zα domain, in charge of recognising Z-RNA, to mimic ADAR1 loss-of-function found in Aicardi-Goutières syndrome but leaving the other functional domains and protein structure unaffected. Defective binding of Z-RNA triggers MDA5/MAVS (mitochondrial antiviral-signalling protein) pathway, in both CRISPR/Cas9 Zα mutant human cell line and generated ADAR1 Zα mutant mice, leading to type-I IFN production. By losing the ADAR1-Z-RNA interaction, the capacity of ADAR1 to edit Z-RNA is also lost, suggesting the mechanism for the spontaneous type-I IFN response. This systemic IFN response does not appear to alter haematopoiesis for mutant mice or to trigger the development of an inflammatory disease, but appears to confer some protection against viral infections as suggested by EMCV (Encephalomyocarditis Virus) lower viral replication. 

Limitations

  • The authors look at the IFN signature in different tissues/cells but do not look at the origin of the systemic IFN response in mutant mice by dissecting the IFN signature. 

  • Although investigating and discarding the role of PKR as sensor for dsRNA, there is no discussion nor experiments about RIG-I.

Significance/Novelty

This preprint explores the mechanism by which non-canonical nucleic acids can be sensed and relates it to a known loss-of-function in a type-I interferonopathy, the Aicardi-Goutières Syndrome. Moreover, the role of the ADAR1 Zα domain on recognising and further allowing the A-to-I editing of dsRNA that derive from SINEs, masking those from immune detection, opens up a wide range of options to further explore the role of Z-RNA and retroelements. 

The target of epigenetic factors in cancer therapy, as suppression of DNA methylation, induces the transcription of retroelements (Nair L et al. Regulation of long non-coding RNAs and genome dynamics by the RNA surveillance machinery. Nat Rev Mol Cell Biol. 2020 Mar;21(3):123-136. doi: 10.1038/s41580-019-0209-0) that if sensed, may help target cancer cells. Therefore, to understand masking, regulation and sensing of the by-products from the transcription of retroelements can provide targets for cancer therapeutics as well as help to modulate the response against retroelements in other pathologies.

 

Credit 

Reviewed by Ester Gea-Mallorquí as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow her on Twitter.