Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L.

TitleReal-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L.
Publication TypeJournal Article
Year of Publication2019
AuthorsChitrakar, A, Rath, S, Donovan, J, Demarest, K, Li, Y, Sridhar, RRao, Weiss, SR, Kotenko, SV, Wingreen, NS, Korennykh, A
JournalProc Natl Acad Sci U S A
Volume116
Issue6
Pagination2103-2111
Date Published2019 02 05
ISSN1091-6490
KeywordsBiosensing Techniques, Cell Line, Endoribonucleases, Humans, Interferon-beta, Interferons, Models, Molecular, Protein Binding, Protein Biosynthesis, Protein Conformation, Protein Interaction Domains and Motifs, Structure-Activity Relationship
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',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.

DOI10.1073/pnas.1818363116
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID30655338
PubMed Central IDPMC6369740
Grant ListR01 GM110161 / GM / NIGMS NIH HHS / United States
R01 AI104887 / AI / NIAID NIH HHS / United States
R01 AI104669 / AI / NIAID NIH HHS / United States
R01 NS081008 / NS / NINDS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
F99 CA212468 / CA / NCI NIH HHS / United States