Edited by Peter Walter, University of California, San Francisco, CA, and approved December 14, 2018 (received for review October 24, 2018)
RNase L is a mammalian enzyme that can stop global protein synthesis during interferon (IFN) response. Cells must balance the need to make IFNs (which are proteins) with the risk of losing cell-wide translation due to RNase L. This balance can be achieved most simply if RNase L is activated late in the IFN response. However, by engineering a biosensor for the RNase L pathway, we show that RNase L activation actually precedes IFN synthesis. Furthermore, translation of IFN 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.
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′,5′-oligoadenylate (2-5A), the natural activator of RNase L. Using this biosensor, 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 and secreted IFNs of types I and III (IFN-β and IFN-λ). Our data suggest that IFNs escape from the action of RNase L on translation. We propose that the 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.
↵1A.C. and S.R. contributed equally to this work.
Author contributions: A.C., S.R., S.V.K., and A.K. designed research; A.C., S.R., J.D., K.D., and R.R.S. performed research; A.C., S.R., Y.L., R.R.S., S.R.W., and S.V.K. contributed new reagents/analytic tools; A.C., S.R., J.D., N.S.W., and A.K. analyzed data; and A.C., S.R., and A.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE120355).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818363116/-/DCSupplemental.
Published under the PNAS license.
