@article {Chitrakar476341, author = {Alisha Chitrakar and Sneha Rath and Jesse Donovan and Kaitlin Demarest and Yize Li and Raghavendra Rao Sridhar and Susan R. Weiss and Sergei V. Kotenko and Ned S. Wingreen and Alexei Korennykh}, title = {Realtime 2-5A kinetics suggests interferons β and λ evade global arrest of translation by RNase L}, elocation-id = {476341}, year = {2018}, doi = {10.1101/476341}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Cells of all mammals recognize double-stranded RNA (dsRNA) as a foreign material. In response, they release interferons (IFNs) and activate a ubiquitously expressed pseudokinase/endoribonuclease RNase L. RNase L executes regulated RNA decay and halts global translation. Here we developed a biosensor for 2{\textquoteright},5{\textquoteright}-oligoadenylate (2-5A), the natural activator of RNase L. We found that 2-5A was acutely synthesized by cells in response to dsRNA sensing, which immediately triggered cellular RNA cleavage by RNase L and arrested host protein synthesis. However, translation-arrested cells still transcribed IFN-stimulated genes (ISGs) and secreted IFNs of types I and III (IFN-β and IFN-λ). Our data suggests that IFNs escape from the action of RNase L on translation. We propose that 2-5A/RNase L pathway serves to rapidly and accurately suppress basal protein synthesis, preserving privileged production of defense proteins of the innate immune system.Significance RNase L is a mammalian enzyme that can stop global protein synthesis during interferon response. Cells must balance the need to make interferons (which are proteins) with the risk to lose cell-wide translation due to RNase L. This balance can most simply be achieved if RNase L was activated late in the interferon response. However, we show by engineering a biosensor for the RNase L pathway, that on the contrary, RNase L activation precedes interferon synthesis. Further, translation of interferons evades the action of RNase L. Our data suggest that RNase L facilitates a switch of protein synthesis from homeostasis to specific needs of innate immune signaling.}, URL = {https://www.biorxiv.org/content/early/2018/11/26/476341}, eprint = {https://www.biorxiv.org/content/early/2018/11/26/476341.full.pdf}, journal = {bioRxiv} }