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Real-Time 2-5A Kinetics Suggest That Interferons Β and Λ Evade Global Arrest of Translation by Rnase L

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Real-Time 2-5A Kinetics Suggest That Interferons Β and Λ Evade Global Arrest of Translation by Rnase L Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L Alisha Chitrakara,1, Sneha Ratha,1, Jesse Donovana, Kaitlin Demaresta, Yize Lib, Raghavendra Rao Sridharc,d, Susan R. Weissb, Sergei V. Kotenkoc,d, Ned S. Wingreena, and Alexei Korennykha,2 aDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544; bDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cDepartment of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103; and dCenter for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103 Edited by Peter Walter, University of California, San Francisco, CA, and approved December 14, 2018 (received for review October 24, 2018) Cells of all mammals recognize double-stranded RNA (dsRNA) as a of a dimeric endoribonuclease active site (21–23). This dimer foreign material. In response, they release interferons (IFNs) and further assembles into high-order oligomers (24) that cleave viral activate a ubiquitously expressed pseudokinase/endoribonuclease RNAs (16, 18) and all components of the translation apparatus, RNase L. RNase L executes regulated RNA decay and halts global including mRNAs (25), tRNAs (26), and 28S/18S rRNAs (27, translation. Here, we developed a biosensor for 2′,5′-oligoadeny- 28). The resulting action of RNase L inhibits global translation, late (2-5A), the natural activator of RNase L. Using this biosensor, which puts all proteins, including IFNs, at risk for arrest during a we found that 2-5A was acutely synthesized by cells in response to cellular response to dsRNA. dsRNA sensing, which immediately triggered cellular RNA cleav- The impact of translational shutdown by RNase L on IFN age by RNase L and arrested host protein synthesis. However, synthesis and paracrine IFN signaling is unknown. Measurements translation-arrested cells still transcribed IFN-stimulated genes of 2-5A/RNase L activity have been limited by the need for and secreted IFNs of types I and III (IFN-β and IFN-λ). Our data biochemical analyses, which are incompatible with live cells. To suggest that IFNs escape from the action of RNase L on translation. address this challenge, we have developed a real-time 2-5A We propose that the 2-5A/RNase L pathway serves to rapidly and biosensor (patent application WO 2017193051 A1) and used it accurately suppress basal protein synthesis, preserving privileged to elucidate the kinetics of 2-5A–mediated RNase L activation production of defense proteins of the innate immune system. and translational arrest occurring during the cellular response to CELL BIOLOGY immunostimulatory dsRNAs. Our biosensor can detect in situ 2- interferon | translation reprogramming | 2-5A | RNase L | RNA decay 5A synthesis in mammalian cells, and thus it provides a hereto- fore missing platform for cell-based applications. These appli- nterferons (IFNs) of type I (α and β) and type III (λ1, λ2, and cations can range from live cell screens for modulators of innate Iλ3) are cytokines secreted by cells after exposure to pathogens immune responses to mechanistic analysis of dsRNA sensing, or internal damage. Both types of IFNs activate transcriptional which we describe in this paper. programs in surrounding tissues to induce the innate immune response. IFN production requires protein synthesis; however, Results during the innate immune response to double-stranded RNA Real-Time 2-5A Dynamics in Live Cells. In the absence of methods to (dsRNA), IFN production is universally accompanied by trans- monitor 2-5A without cell disruption, the cellular dynamics of lational arrest. Inhibition of protein synthesis arises in part from activation of the dsRNA-dependent protein kinase R (PKR) and Significance in part from signaling by conserved small RNAs that contain 2′,5′-linked oligoadenylates (2-5A) (1–4). The action of 2-5A is RNase L is a mammalian enzyme that can stop global protein sufficient for the arrest of translation independent of PKR, and synthesis during interferon (IFN) response. Cells must balance at least in some cell lines, 2-5A is the main cause of translational the need to make IFNs (which are proteins) with the risk of arrest (5). losing cell-wide translation due to RNase L. This balance can be In human cells, 2-5A is synthesized by three enzymes: oli- achieved most simply if RNase L is activated late in the IFN goadenylate synthetase 1 (OAS1), OAS2, and OAS3 (OASs), response. However, by engineering a biosensor for the RNase L which function as cytosolic dsRNA sensors using dsRNA binding pathway, we show that RNase L activation actually precedes for activation (6, 7). The activity of the OASs is normally low to IFN synthesis. Furthermore, translation of IFN evades the action allow for housekeeping protein synthesis, but it increases in the of RNase L. Our data suggest that RNase L facilitates a switch of presence of viral or host dsRNA molecules (8). 2-5A has an protein synthesis from homeostasis to specific needs of innate antiviral effect, against which some viruses have evolved 2-5A immune signaling. antagonist genes that are essential for infection (9–16). The 2-5A system is also a surveillance pathway for endogenous 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 double-stranded RNAs (dsRNAs) from mammalian genomes. reagents/analytic tools; A.C., S.R., J.D., N.S.W., and A.K. analyzed data; and A.C., S.R., and Cells with adenosine deaminase 1 deficiency accumulate self- A.K. wrote the paper. dsRNA that promotes 2-5A–driven apoptosis (8). 2-5A synthesis The authors declare no conflict of interest. in the presence of low amounts of endogenous dsRNAs does not This article is a PNAS Direct Submission. cause cell death, but rather functions as a suppressor of adhe- Published under the PNAS license. sion, proliferation, migration, and prostate cancer metastasis (17, Data deposition: The data reported in this paper have been deposited in the Gene Ex- 18). In addition, activation of the 2-5A system also blocks se- pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. cretion of milk proteins and stops lactation, presumably as a GSE120355). mechanism to prevent passing infection via breast feeding (19). 1A.C. and S.R. contributed equally to this work. All the effects of 2-5A arise from the action of a single 2To whom correspondence should be addressed. Email: [email protected]. mammalian 2-5A receptor, pseudokinase-endoribonuclease L This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (RNase L) (20). 2-5A binds to the ankyrin-repeat (ANK) domain 1073/pnas.1818363116/-/DCSupplemental. of RNase L and promotes its oligomerization and the formation www.pnas.org/cgi/doi/10.1073/pnas.1818363116 PNAS Latest Articles | 1of9 Downloaded by guest on September 28, 2021 this second messenger are poorly understood. Here we devel- tyrosine (24) (Fig. 2 B and C). The reporter V6 had sufficient oped a biosensor for continuous and noninvasive 2-5A moni- sensitivity to detect low amounts of 2-5A purified from human toring in live cells. The biosensor was designed based on the cells treated with poly-inosine/poly-cytidine (poly-IC) dsRNA (SI crystal structures of the cellular 2-5A receptor RNase L (22, 24) Appendix, Fig. S1A). These reporter measurements agreed closely (Fig. 1A), indicating that the N-terminal ANK domain of RNase with the standard endoribonuclease readout based on rRNA L is sufficient for 2-5A sensing and provides a minimal di- cleavage (SI Appendix, Fig. S1B). merization module (24). In a single ANK protomer, the N and C To determine whether V6 was sufficiently bright and stable in termini in cis are separated, but on dimerization of two ANK live cells, we expressed FLAG-tagged V6 in HeLa cells and domains, which bind notably head-to-tail, the N and C termini stimulated these reporter cells with poly-IC. The poly-IC treat- become positioned in trans next to each other (Fig. 1B). We used ment conditions were selected to produce cleavage of 28S rRNA this in cis vs in trans N–C distance decrease to drive a dual split- in the conventional endpoint assay using cell disruption (22). 28S luciferase sensor. rRNA cleavage was noticeable after 1 h of poly-IC treatment and This combinatorially optimized sensor has two halves, con- increased further after 3 and 4 h (Fig. 3A). HeLa cells expressing sisting of the core ANK domain fused to a modified split firefly WT FLAG-V6 exhibited a time-dependent increase in lumi- luciferase (Fluc) (29) (Fig. 1B). We modified Fluc by replacing nescence in the presence of cell-permeable D-luciferin ethyl ester the published overlapping split junction N416/C415 with a non- (Fig. 3B and SI Appendix, Fig. S1C). The luminescence increase overlapping junction (Fig. 2A). Due to the head-to-tail structure, began at approximately 30 min of poly-IC treatment and be- the sensor was encoded as one polypeptide, which simplified its fore the appearance of visible 28S rRNA cleavage. HeLa cells use compared with usual two-protein split systems. We opti- expressing control FLAG-V6-Y312A produced no increase in mized the reporter by engineering the linker regions and selected luminescence, confirming that WT V6 detects cellular 2-5A in variant V6 with the highest luminescence response to 2-5A for real time. further work (Fig. 2A). We determined that V6 was suitable for Further evidence of specific 2-5A detection was obtained in 2-5A detection over a range of 2-5A and V6 concentrations from cells in which 2-5A synthetases were knocked out.
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