Distinguishing self from non-self RNA by editing-specific inosine patterns

article Distinguishing self from non-self RNA by editing-specific inosine patterns published yes Rajagopal Varada author Alina F. Leuchtenberger author Cornelia Vesely author Beata M Kaczmarek author 36FA4AFA-F248-11E8-B48F-1D18A9856A87 Hamid Mansouri Khosravi author Therese C. Mandl author Katarina Milanovic author Kasra Honarmand Tamizkar author Vinod Rajendra author Hannes Senoner author Linda Steinbichl author Marija Borojevic author Andy Sombke author Katy Schmidt author Margret Eckhard author Ivo L. Hofacker author Carl Walkley author Jacki E. Heraud-Farlow author Ernesto Picardi author Carrie A Bernecky author 2CB9DFE2-F248-11E8-B48F-1D18A9856A870000-0003-0893-7036 Michael F. Jantsch author CaBe department GradSch department RNAdeco: decorating RNA for a purpose/ P03- Roles of A-to-I editing in dsRNA recognition project The cytoplasmic antiviral sensor MDA5 is activated by double-stranded RNAs. Endogenous double-stranded RNAs are modified by the A-to-I RNA-editing ADAR family to prevent activation of MDA5. In vivo, cytoplasmic ADAR1p150 is critically required to suppress MDA5 activation, yet the editing signature of all ADAR isoforms is strongly overlapping in mice. Further, it is not clear how A-to-I modifications in dsRNA prevent MDA5 activation. Here we show that 3′ UTRs harboring inverted repeats activate MDA5 in vitro and in cells. In vitro editing by either ADAR isoform leads to editing at overlapping hotspot regions and prevents MDA5 activation in vitro and in cells. Remarkably, only inosines introduced by RNA editing are capable of suppressing MDA5 activation, while replacing guanosines with inosines during in vitro transcription has no impact on MDA5 activation. A comparison of inosines introduced by ADAR1p150 in vitro, in cells, and in vivo suggests that a small number of A-to-I conversions may be critically required to suppress MDA5 activation. As those critical editing events are predominantly altering A:U basepairs into I:U wobble basepairs, we suggest that the helical distortion introduced by those wobble pairs may prevent MDA5 polymerization and thus downstream activation of the type I interferon response. https://research-explorer.ista.ac.at/download/22772/22872/2026_NucleicAcidsResearch_Varada.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ Oxford University Press2026 eng Nucleic Acids Research 1362-4962 4263512510.1093/nar/gkag845 5416 R. Varada, A.F. Leuchtenberger, C. Vesely, B.M. Kaczmarek, H. Mansouri Khosravi, T.C. Mandl, K. Milanovic, K. Honarmand Tamizkar, V. Rajendra, H. Senoner, L. Steinbichl, M. Borojevic, A. Sombke, K. Schmidt, M. Eckhard, I.L. Hofacker, C. Walkley, J.E. Heraud-Farlow, E. Picardi, C. Bernecky, M.F. Jantsch, Nucleic Acids Research 54 (2026). Varada, Rajagopal, Alina F. Leuchtenberger, Cornelia Vesely, Beata M Kaczmarek, Hamid Mansouri Khosravi, Therese C. Mandl, Katarina Milanovic, et al. “Distinguishing Self from Non-Self RNA by Editing-Specific Inosine Patterns.” Nucleic Acids Research. Oxford University Press, 2026. <a href="https://doi.org/10.1093/nar/gkag845">https://doi.org/10.1093/nar/gkag845</a>. Varada R, Leuchtenberger AF, Vesely C, Kaczmarek BM, Mansouri Khosravi H, Mandl TC, Milanovic K, Honarmand Tamizkar K, Rajendra V, Senoner H, Steinbichl L, Borojevic M, Sombke A, Schmidt K, Eckhard M, Hofacker IL, Walkley C, Heraud-Farlow JE, Picardi E, Bernecky C, Jantsch MF. 2026. Distinguishing self from non-self RNA by editing-specific inosine patterns. Nucleic Acids Research. 54(16), gkag845. Varada R, Leuchtenberger AF, Vesely C, et al. Distinguishing self from non-self RNA by editing-specific inosine patterns. Nucleic Acids Research. 2026;54(16). doi:<a href="https://doi.org/10.1093/nar/gkag845">10.1093/nar/gkag845</a> Varada, Rajagopal, et al. “Distinguishing Self from Non-Self RNA by Editing-Specific Inosine Patterns.” Nucleic Acids Research, vol. 54, no. 16, gkag845, Oxford University Press, 2026, doi:<a href="https://doi.org/10.1093/nar/gkag845">10.1093/nar/gkag845</a>. Varada, R., Leuchtenberger, A. F., Vesely, C., Kaczmarek, B. M., Mansouri Khosravi, H., Mandl, T. C., … Jantsch, M. F. (2026). Distinguishing self from non-self RNA by editing-specific inosine patterns. Nucleic Acids Research. Oxford University Press. <a href="https://doi.org/10.1093/nar/gkag845">https://doi.org/10.1093/nar/gkag845</a> R. Varada et al., “Distinguishing self from non-self RNA by editing-specific inosine patterns,” Nucleic Acids Research, vol. 54, no. 16. Oxford University Press, 2026. 227722026-08-30T22:01:44Z2026-09-09T11:31:04Z