Review
ADAR RNA Modifications, the Epitranscriptome and Innate Immunity

https://doi.org/10.1016/j.tibs.2021.02.002Get rights and content
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Highlights

  • Epitranscriptomic RNA modifications act as marks of innate immune self in RNA; they are critical in current mRNA vaccines.

  • Studies on adenosine-to-inosine deamination by ADAR enzymes show how inosine acts as a mark of self-RNA by altering the structure of double-stranded (ds)RNA to prevent aberrant activation of antiviral RIG-I–like receptors (RLRs).

  • Self-marks in RNA threshold and balance innate immune defences against infections; ADAR mutations cause inflammatory diseases.

  • Helicase domains of RLRs scan along perfect dsRNA, and RLRs form signalling complexes cooperatively; base mismatches or I-U base pairs cause RLR disassociation from RNA, and the ancestral helicase domains of DICER proteins probably originated this mechanism.

  • Knockdown of ADAR1, and potentially also small molecule inhibitors of ADAR1, kill some cancer cells directly and strongly enhance killing of others by immune checkpoint blockade.

Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosine-to-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I–like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer.

Keywords

RNA editing
double-stranded RNA (dsRNA)
pattern recognition receptors (PRRs)
interferon
antiviral responses
autoinflammatory disease

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