Realtime 2-5A kinetics suggests interferons ß and ? evade global arrest of translation by RNase L

Alisha Chitrakar; Sneha Rath; Jesse Donovan; Kaitlin Demarest; Yize Li; Raghavendra Rao Sridhar; Susan R. Weiss; Sergei V. Kotenko; Ned S. Wingreen; Alexei Korennykh

The action of RNase L resembles arrest of the initiation step, which can be accompanied by a characteristic collapse of polysomes 25 . A similar polysomal collapse is observed upon activation of integrated stress response (ISR) that employs serine/threonine kinases to phosphorylate and inactivate the translation initiation factor eIF2 44 . In the ISR, the arrest of translational initiation can be bypassed by mRNAs encoding stress proteins, such as ATF4 and IBTK due to the presence of 5' uORFs that increase translation under conditions of limiting initiation 45 . Although it remains unclear how IFNs bypass RNase L and whether they may use a related route 46 The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/476341 doi: bioRxiv preprint sense dsRNA at a distance from the site of RNase L action. The range of OAS-RNase L communication depends on efficiency of 2-5A diffusion, which occurs with rates sufficient for 2-5A equilibration between the nucleus and the cytosol faster than the rate of 2-5A production. Therefore, RNase L is poised to respond to 2-5A from cytoplasmic and nuclear OASs, suggesting that detection of dsRNA in both compartments is a likely biologic function of cytosolic RNase L.