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

However, during innate immune response to double-stranded RNA (dsRNA), IFN production is universally accompanied by translational arrest. Inhibition of protein synthesis arises in part due to activation of the dsRNA-dependent protein kinase R (PKR), and in part due to signaling by conserved small RNAs that contain 2',5'-linked oligoadenylates (2-5A) 1-4 . The action of 2-5A is sufficient for arrest of translation, independent of PKR, and at least in some cell lines 2-5A is the main cause of translational arrest 5 . In human cells, 2-5A is synthesized by three enzymes: oligoadenylate synthetase 1 (OAS1), OAS2 and OAS3 (OASs), which function as cytosolic dsRNA sensors using dsRNA binding for activation 6, 7 . The activity of the OASs is normally low to allow housekeeping protein synthesis, but it increases in the presence of viral or host dsRNA molecules 8 . 2-5A has a strong antiviral effect, against which many viruses have evolved 2-5A antagonist genes that are essential for infection 9-16 . proteins and stops lactation, presumably as a mechanism to prevent passing infection via breast feeding 19 .