Title | Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Chitrakar, A, Rath, S, Donovan, J, Demarest, K, Li, Y, Sridhar, RRao, Weiss, SR, Kotenko, SV, Wingreen, NS, Korennykh, A |
Journal | Proc Natl Acad Sci U S A |
Volume | 116 |
Issue | 6 |
Pagination | 2103-2111 |
Date Published | 2019 Feb 05 |
ISSN | 1091-6490 |
Keywords | Biosensing 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 | <p>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.</p> |
DOI | 10.1073/pnas.1818363116 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 30655338 |
PubMed Central ID | PMC6369740 |
Grant List | R01 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 |