Circular RNAs (circRNAs), which are generated through back-splicing of pre-mRNAs, are stable and widely expressed, but their biological role has remained a mystery. Writing in Cell, Liu et al. now show that circRNAs bind to and thereby ‘shield’ protein kinase R (PKR), a pattern recognition receptor with antiviral function that is normally activated by double-stranded RNA (dsRNA).
Previous studies had implicated circRNAs in innate immune regulation. For example, it was found that the biogenesis of nascent circRNAs is reduced upon viral infection and that enforced expression of circRNAs via plasmids can facilitate viral infection of human cells. Moreover, patients with a genetic defect leading to the accumulation of intron-lariat-derived RNA circles are more susceptible to viral infections.
The authors now demonstrate that stimulation of HeLa cells with poly(I:C) or infection with the RNA virus encephalomyocarditis virus induces RNaseL activation, which leads to circRNA degradation and the release of PKR inhibition. The key role of RNaseL in degrading circRNA was confirmed in RNaseL-knockout and RNaseL-knockdown cells and by using a synthetic RNaseL activator.
PKR is known to undergo auto-phosphorylation in response to activation by long dsRNAs (>33 bp), but this activation is blocked by short dsRNAs (16–33 bp). The authors show that circRNAs, but not their linear cognate RNAs, inhibit dsRNA-induced phosphorylation of PKR. Structural analysis of the circRNAs revealed that PKR suppression was independent of their sequence but required the presence of dsRNA regions, which were typically 16–26 bp in length.
Interestingly, the authors also found that peripheral blood mononuclear cells derived from patients with systemic lupus erythematosus (SLE) contained less circRNAs, had spontaneous RNaseL activation and showed enhanced PKR phosphorylation compared with controls. Overexpression of circRNAs, but not their linear counterparts, attenuated aberrant PKR activation in these cells.
“circRNAs bind to and thereby ‘shield’ protein kinase R (PKR), a pattern recognition receptor with antiviral function”
These studies demonstrate that circRNAs can modulate innate immunity to viruses and reveal an unexpected connection between circRNAs and the autoimmune disease SLE.
Liu, C.-X. et al. Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell https://doi.org/10.1016/j.cell.2019.03.046 (2019)
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Flemming, A. The enigma of circular RNA. Nat Rev Immunol 19, 351 (2019). https://doi.org/10.1038/s41577-019-0173-0
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