RNAs containing modified nucleotides fail to trigger RIG-I conformational changes for innate immune signaling
Open accessAbstract
UNLABELLED: Invading pathogen nucleic acids are recognized and bound by cytoplasmic (retinoic acid-inducible gene I [RIG-I]-like) and membrane-bound (Toll-like) pattern recognition receptors to activate innate immune signaling. Modified nucleotides, when present in RNA molecules, diminish the magnitude of these signaling responses. However, mechanisms explaining the blunted signaling have not been elucidated. In this study, we used several independent biological assays, including inhibition of virus replication, RIG-I:RNA binding assays, and limited trypsin digestion of RIG-I:RNA complexes, to begin to understand how RNAs containing modified nucleotides avoid or suppress innate immune signaling. The experiments were based on a model innate immune activating RNA molecule, the polyU/UC RNA domain of hepatitis C virus, which was transcribed in vitro with canonical nucleotides or with one of eight modified nucleotides. The approach revealed signature assay responses associated with individual modified nucleotides or classes of modified nucleotides. For example, while both N-6-methyladenosine (m6A) and pseudouridine nucleotides correlate with diminished signaling, RNA containing m6A modifications bound RIG-I poorly, while RNA containing pseudouridine bound RIG-I with high affinity but failed to trigger the canonical RIG-I conformational changes associated with robust signaling. These data advance understanding of RNA-mediated innate immune signaling, with additional relevance for applying nucleotide modifications to RNA therapeutics. IMPORTANCE: The innate immune system provides the first response to virus infections and must distinguish between host and pathogen nucleic acids to mount a protective immune response without activating autoimmune responses. While the presence of nucleotide modifications in RNA is known to correlate with diminished innate immune signaling, the underlying mechanisms have not been explored. The data reported here are important for defining mechanistic details to explain signaling suppression by RNAs containing modified nucleotides. The results suggest that RNAs containing modified nucleotides interrupt signaling at early steps of the RIG-I-like innate immune activation pathway and also that nucleotide modifications with similar chemical structures can be organized into classes that suppress or evade innate immune signaling steps. These data contribute to defining the molecular basis for innate immune signaling suppression by RNAs containing modified nucleotides. The results have important implications for designing therapeutic RNAs that evade innate immune detection.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Incorporating naturally occurring modified nucleotides into in vitro transcribed mRNA drastically reduces its innate immune activity.
“by incorporating naturally occurring modified nucleotides into the IVT mRNA, its innate immune activity could be drastically reduced [6,7]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [7]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Karikó, K., Buckstein, M., Ni, H., & Weissman, D. (2005) · Immunity · doi:10.1016/j.immuni.2005.06.008 · Cited by 2,728 · see citing works
Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., et al. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.08.012 · Cited by 2,662 · see citing works
5'-Triphosphate RNA Is the Ligand for RIG-I
Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.-K., Schlee, M., et al. (2006) · Science · doi:10.1126/science.1132505 · Cited by 2,474 · see citing works
RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates
Pichlmair, A., Schulz, O., Tan, C. P., Näslund, T. I., Liljeström, P., Weber, F., & Reis e Sousa, C. (2006) · Science · doi:10.1126/science.1132998 · Cited by 2,210 · see citing works
TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity
Gack, M. U., Shin, Y. C., Joo, C.-H., Urano, T., Liang, C., Sun, L., Takeuchi, O., Akira, S., Chen, Z. J., Inoue, S., et al. (2007) · Nature · doi:10.1038/nature05732 · Cited by 1,683 · see citing works
Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA
Squires, J. E., Patel, H. R., Nousch, M., Sibbritt, T., Humphreys, D. T., Parker, B. J., Suter, C. M., & Preiß, T. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks144 · Cited by 1,011 · see citing works
MODOMICS: a database of RNA modification pathways—2013 update
Machnicka, M. A., Milanowska, K., Oglou, O. O., Purta, E., Kurkowska, M., Olchowik, A., Januszewski, W., Kalinowski, S., Dunin-Horkawicz, S., Rother, K. M., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1007 · Cited by 1,003 · see citing works
2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members
Daffis, S., Szretter, K. J., Schriewer, J. M., Li, J., Youn, S., Errett, J. S., Lin, T., Schneller, S. W., Züst, R., Dong, H., et al. (2010) · Nature · doi:10.1038/nature09489 · Cited by 910 · see citing works
Sumpter, R., Loo, Y., Foy, E. M., Li, K., Yoneyama, M., Fujita, T., Lemon, S. M., & Gale, M. (2005) · Journal of Virology · doi:10.1128/jvi.79.5.2689-2699.2005 · Cited by 900 · see citing works
Karikó, K., Muramatsu, H., Ludwig, J., & Weissman, D. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr695 · Cited by 898 · see citing works
Züst, R., Cervantes-Barragan, L., Habjan, M., Maier, R., Neuman, B. W., Ziebuhr, J., Szretter, K. J., Baker, S. C., Barchet, W., Diamond, M. S., et al. (2011) · Nature Immunology · doi:10.1038/ni.1979 · Cited by 811 · see citing works
Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA
Saito, T., Owen, D. M., Jiang, F., Marcotrigiano, J., & Gale, M. (2008) · Nature · doi:10.1038/nature07106 · Cited by 745 · see citing works
Self-citationStructural Basis for the Activation of Innate Immune Pattern-Recognition Receptor RIG-I by Viral RNA
Kowalinski, E., Lunardi, T., McCarthy, A. A., Louber, J., Brunel, J., Grigorov, B., Gerlier, D., & Cusack, S. (2011) · Cell · doi:10.1016/j.cell.2011.09.039 · Cited by 689 · see citing works
Phosphorothioates, Essential Components of Therapeutic Oligonucleotides
Eckstein, F. (2014) · Nucleic Acid Therapeutics · doi:10.1089/nat.2014.0506 · Cited by 684 · see citing works
Zeng, W., Sun, L., Jiang, X., Chen, X., Hou, F., Adhikari, A., Xu, M., & Chen, Z. J. (2010) · Cell · doi:10.1016/j.cell.2010.03.029 · Cited by 613 · see citing works
Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates
Goubau, D., Schlee, M., Deddouche, S., Pruijssers, A. J., Zillinger, T., Goldeck, M., Schuberth, C., Van der Veen, A. G., Fujimura, T., Rehwinkel, J., et al. (2014) · Nature · doi:10.1038/nature13590 · Cited by 557 · see citing works
Nonself RNA-Sensing Mechanism of RIG-I Helicase and Activation of Antiviral Immune Responses
Takahasi, K., Yoneyama, M., Nishihori, T., Hirai, R., Kumeta, H., Narita, R., Gale, M., Inagaki, F., & Fujita, T. (2008) · Molecular Cell · doi:10.1016/j.molcel.2007.11.028 · Cited by 474 · see citing works
Structural basis of RNA recognition and activation by innate immune receptor RIG-I
Jiang, F., Ramanathan, A., Miller, M. T., Tang, G., Gale, M., Patel, S. S., & Marcotrigiano, J. (2011) · Nature · doi:10.1038/nature10537 · Cited by 429 · see citing works
Self-citation5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I
Schmidt, A., Schwerd, T., Hamm, W., Hellmuth, J. C., Cui, S., Wenzel, M., Hoffmann, F. S., Michallet, M.-C., Besch, R., Hopfner, K.-P., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900971106 · Cited by 398 · see citing works
Devarkar, S. C., Wang, C., Miller, M. T., Ramanathan, A., Jiang, F., Khan, A. G., Patel, S. S., & Marcotrigiano, J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1515152113 · Cited by 357 · see citing works
Self-citationRNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise?
Bobbin, M. L., & Rossi, J. J. (2016) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103633 · Cited by 352 · see citing works
Schuberth-Wagner, C., Ludwig, J., Bruder, A. K., Herzner, A., Zillinger, T., Goldeck, M., Schmidt, T., Schmid-Burgk, J. L., Kerber, R., Wolter, S., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.015 · Cited by 311 · see citing works
Schonborn, J., Oberstraβ, J., Breyel, E., Tittgen, J., Schumacher, J., & Lukacs, N. (1991) · Nucleic Acids Research · doi:10.1093/nar/19.11.2993 · Cited by 303 · see citing works
Krug, R. M., Morgan, M. A., & Shatkin, A. J. (1976) · Journal of Virology · doi:10.1128/jvi.20.1.45-53.1976 · Cited by 289 · see citing works
A mutant T7 RNA polymerase as a DNA polymerase.
Sousa, R., & Padilla, R. M. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00140.x · Cited by 288 · see citing works
RIG-I Forms Signaling-Competent Filaments in an ATP-Dependent, Ubiquitin-Independent Manner
Peisley, A., Wu, B., Yao, H., Walz, T., & Hur, S. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.07.024 · Cited by 236 · see citing works
N6-methyl-adenosine modification in messenger and long non-coding RNA
Pan, T. (2013) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.12.006 · Cited by 208 · see citing works
Localization of N6-methyladenosine in the Rous sarcoma virus genome
BEEMON, K. L., & Keith, J. M. (1977) · Journal of Molecular Biology · doi:10.1016/0022-2836(77)90047-x · Cited by 179 · see citing works
Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments
Peisley, A., Jo, M. H., Lin, C., Wu, B., Orme-Johnson, M., Walz, T., Hohng, S., & Hur, S. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208618109 · Cited by 170 · see citing works
Nucleotide Sequences and Modifications That Determine RIG-I/RNA Binding and Signaling Activities
Uzri, D., & Gehrke, L. (2009) · Journal of Virology · doi:10.1128/jvi.02449-08 · Cited by 155 · see citing works
Self-citationBartlett, D. W., & Davis, M. E. (2006) · Biotechnology and Bioengineering · doi:10.1002/bit.21285 · Cited by 154 · see citing works
2′-O Methylation of Internal Adenosine by Flavivirus NS5 Methyltransferase
Dong, H., Chang, D. C.-H., Hua, M. H. C., Lim, S. P., Chionh, Y. H., Hia, F., Lee, Y. H., Kukkaro, P., Lok, S., Dedon, P. C., et al. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002642 · Cited by 154 · see citing works
Suppression of immunostimulatory siRNA-driven innate immune activation by 2′-modified RNAs
Sioud, M., Furset, G., & Cekaite, L. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.06.177 · Cited by 149 · see citing works
Flow Cytometry-Based Assay for Titrating Dengue Virus
Lambeth, C., White, L., Johnston, R. E., & de Silva, A. M. (2005) · Journal of Clinical Microbiology · doi:10.1128/jcm.43.7.3267-3272.2005 · Cited by 149 · see citing works
In Vivo Ligands of MDA5 and RIG-I in Measles Virus-Infected Cells
Runge, S., Sparrer, K. M. J., Lässig, C., Hembach, K., Baum, A., García‐Sastre, A., Söding, J., Conzelmann, K., & Hopfner, K. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004081 · Cited by 142 · see citing works
A structure-based model of RIG-I activation
Kolakofsky, D., Kowalinski, E., & Cusack, S. (2012) · RNA · doi:10.1261/rna.035949.112 · Cited by 142 · see citing works
Nallagatla, S. R., & Bevilacqua, P. C. (2008) · RNA · doi:10.1261/rna.1007408 · Cited by 137 · see citing works
Biological Activity and Biotechnological Aspects of Locked Nucleic Acids
Lundin, K. E., Højland, T., Hansen, B. R., Persson, R., Bramsen, J. B., Kjems, J., Koch, T., Wengel, J., & Smith, C. I. E. (2013) · Advances in genetics · doi:10.1016/b978-0-12-407676-1.00002-0 · Cited by 109 · see citing works
Uridine Composition of the Poly-U/UC Tract of HCV RNA Defines Non-Self Recognition by RIG-I
Schnell, G., Loo, Y., Marcotrigiano, J., & Gale, M. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002839 · Cited by 102 · see citing works
Self-citationATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA
Lässig, C., Matheisl, S., Sparrer, K. M. J., Mann, C. C. D. O., Moldt, M., Patel, J. R., Goldeck, M., Hartmann, G., García‐Sastre, A., Hornung, V., et al. (2015) · eLife · doi:10.7554/elife.10859 · Cited by 96 · see citing works
RIG-I-like receptors and autoimmune diseases
Kato, H., & Fujita, T. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2015.10.002 · Cited by 87 · see citing works
Interaction of R17 Coat Protein With Its RNA Binding Site For Translational Repression
Uhlenbeck, O. C., Carey, J., Romaniuk, P. J., Lowary, P. T., & Beckett, D. (1983) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.1983.10507460 · Cited by 68 · see citing works
The Epitranscriptome and Innate Immunity
O’Connell, M. A., Mannion, N., & Keegan, L. P. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005687 · Cited by 65 · see citing works
Establishing the role of ATP for the function of the RIG-I innate immune sensor
Rawling, D., Fitzgerald, M. E., & Pyle, A. M. (2015) · eLife · doi:10.7554/elife.09391 · Cited by 63 · see citing works
Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5
Louber, J., Brunel, J., Uchikawa, E., Cusack, S., & Gerlier, D. (2015) · BMC Biology · doi:10.1186/s12915-015-0166-9 · Cited by 54 · see citing works
RIG-I ATPase Activity and Discrimination of Self-RNA versus Non-Self-RNA
Anchisi, S., Guerra, J., & Garcin, D. (2015) · mBio · doi:10.1128/mbio.02349-14 · Cited by 52 · see citing works
An expanding universe of mRNA modifications
Jaffrey, S. R. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2911 · Cited by 43 · see citing works
Uzri, D., & Greenberg, H. B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069825 · Cited by 37 · see citing works
Kell, A. M., Stoddard, M. B., Li, H., Marcotrigiano, J., Shaw, G. M., & Gale, M. (2015) · Journal of Virology · doi:10.1128/jvi.01964-15 · Cited by 34 · see citing works
Self-citationBase Modification Strategies to Modulate Immune Stimulation by an siRNA
Valenzuela, R., Suter, S. R., Ball‐Jones, A. A., Ibarra‐Soza, J. M., Zheng, Y., & Beal, P. A. (2014) · ChemBioChem · doi:10.1002/cbic.201402551 · Cited by 33 · see citing works
Structural insights into the activation of RIG‐I, a nanosensor for viral RNAs
Jiang, Q., & Chen, Z. J. (2011) · EMBO Reports · doi:10.1038/embor.2011.239 · Cited by 32 · see citing works
Nallagatla, S. R., Jones, C. N., Ghosh, S., Sharma, S. D., Cameron, C. E., Spremulli, L. L., & Bevilacqua, P. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057905 · Cited by 30 · see citing works
N6-Methylated Adenosine in RNA: From Bacteria to Humans
Владимирович, С. П., Golovina, A. Y., Osterman, I. А., Nesterchuk, M. V., Sergeeva, O. V., Chugunova, A. A., Evfratov, S. A., Andreyanova, E. S., Pletnev, P. I., Laptev, I. G., et al. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.12.013 · Cited by 30 · see citing works
Conformational rearrangements of RIG-I receptor on formation of a multiprotein:dsRNA assembly
Beckham, S. A., Brouwer, J. M., Roth, A., Wang, D., Sadler, A. J., John, M., Jahn‐Hofmann, K., Williams, B. R. G., Wilce, J. A., & Wilce, M. C. J. (2013) · Nucleic Acids Research · doi:10.1093/nar/gks1477 · Cited by 27 · see citing works
Segmented negative-strand RNA viruses and RIG-I: divide (your genome) and rule
Weber, M., & Weber, F. (2014) · Current Opinion in Microbiology · doi:10.1016/j.mib.2014.05.002 · Cited by 24 · see citing works
Weber, M., & Weber, F. (2014) · Journal of Visualized Experiments · doi:10.3791/51415 · Cited by 12 · see citing works
Kowolinski, E. (2010) · Europe PMC (PubMed Central) · Cited by 1 · see citing works
Flagged first, then by citations
1 of the 58 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
N6-Methyladenosine Modification Controls Circular RNA Immunity
Chen, Y. G., Chen, R., Ahmad, S., Verma, R., Kasturi, S. P., Amaya, L., Broughton, J. P., Kim, J., Cadena, C., Pulendran, B., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.016 · Cited by 572 · see citing works
Innate immune mechanisms of mRNA vaccines
Verbeke, R., Hogan, M. J., Loré, K., & Pardi, N. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.014 · Cited by 518 · see citing works
The dawn of mRNA vaccines: the COVID-19 case
Verbeke, R., Lentacker, I., De Smedt, S. C., & Dewitte, H. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.03.043 · Cited by 504 · see citing works
Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation
Wang, H., Hu, X., Huang, M., Liu, J., Gu, Y. H., Ma, L., Zhou, Q., & Cao, X. (2019) · Nature Communications · doi:10.1038/s41467-019-09903-6 · Cited by 505 · see citing works
RNA Circularization Diminishes Immunogenicity and Can Extend Translation Duration In Vivo
Wesselhoeft, R. A., Kowalski, P. S., Parker-Hale, F. C., Huang, Y., Bisaria, N., & Anderson, D. G. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.02.015 · Cited by 482 · see citing works
Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines
Nance, K. D., & Meier, J. L. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00197 · Cited by 466 · see citing works
m6A modification controls the innate immune response to infection by targeting type I interferons
Winkler, R., Gillis, E., Lasman, L., Safra, M., Geula, S., Soyris, C., Nachshon, A., Tai-Schmiedel, J., Friedman, N., Le‐Trilling, V. T. K., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0275-z · Cited by 454 · see citing works
RIG-I and Other RNA Sensors in Antiviral Immunity
Chow, K. T., Gale, M., & Loo, Y. (2018) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042617-053309 · Cited by 429 · see citing works
The RNA modification N6-methyladenosine as a novel regulator of the immune system
Shulman, Z., & Stern‐Ginossar, N. (2020) · Nature Immunology · doi:10.1038/s41590-020-0650-4 · Cited by 429 · see citing works
Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response
Linares-Fernández, S., Lacroix, C., Exposito, J.-Y., & Verrier, B. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.10.002 · Cited by 376 · see citing works
Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5
Brisse, M. E., & Ly, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01586 · Cited by 361 · see citing works
Impact of mRNA chemistry and manufacturing process on innate immune activation
Nelson, J., Sorensen, E. W., Mintri, S., Rabideau, A. E., Zheng, W., Besin, G., Khatwani, N., Su, S. V., Miracco, E. J., Issa, W. J., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz6893 · Cited by 354 · see citing works
Freyn, A. W., Ramos da Silva, J., Rosado, V. C., Bliss, C. M., Pine, M., Mui, B. L., Tam, Y. K., Madden, T. D., de Souza Ferreira, L. C., Weissman, D., et al. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.04.018 · Cited by 299 · see citing works
A Review in Research Progress Concerning m6A Methylation and Immunoregulation
Zhang, C., Fu, J., & Zhou, Y. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00922 · Cited by 281 · see citing works
N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I
Lu, M., Zhang, Z. S., Xue, M., Zhao, B. S., Harder, O. E., Li, A., Liang, X., Gao, T. Z., Xu, Y., Zhou, J., et al. (2020) · Nature Microbiology · doi:10.1038/s41564-019-0653-9 · Cited by 277 · see citing works
Li, N., Hui, H., Bray, B., Gonzalez, G. M., Zeller, M., Anderson, K. G., Knight, R. D., Smith, D. M., Wang, Y., Carlin, A. F., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109091 · Cited by 277 · see citing works
Vaidyanathan, S., Azizian, K. T., Haque, A. K. M. A., Henderson, J. M., Hendel, A., Shore, S., Antony, J. S., Hogrefe, R. I., Kormann, M. S. D., Porteus, M. H., et al. (2018) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2018.06.010 · Cited by 262 · see citing works
Regulation and Function of RNA Pseudouridylation in Human Cells
Borchardt, E. K., Martínez, N. M., & Gilbert, W. V. (2020) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043830 · Cited by 242 · see citing works
An engineered T7 RNA polymerase that produces mRNA free of immunostimulatory byproducts
Dousis, A. D., Ravichandran, K. R., Hobert, E. M., Moore, M. J., & Rabideau, A. E. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01525-6 · Cited by 238 · see citing works
Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication
Courtney, D., Kennedy, E. M., Dumm, R. E., Bogerd, H. P., Tsai, K., Heaton, N. S., & Cullen, B. R. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.08.004 · Cited by 229 · see citing works
The role of m6A modification in physiology and disease
Yang, C., Hu, Y., Zhou, B., Bao, Y., Li, Z., Gong, C., Yang, H., Wang, S., & Xiao, Y. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-03143-z · Cited by 200 · see citing works
Hesser, C. R., Karijolich, J. J., Dominissini, D., He, C., & Glaunsinger, B. A. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1006995 · Cited by 193 · see citing works
Circular RNAs as Therapeutic Agents and Targets
Holdt, L. M., Kohlmaier, A., & Teupser, D. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01262 · Cited by 187 · see citing works
Zhang, Y., Wang, X., Zhang, X., Wang, J., Ma, Y., Zhang, L., & Cao, X. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1812536116 · Cited by 186 · see citing works
Epigenetic and epitranscriptomic regulation of viral replication
Tsai, K., & Cullen, B. R. (2020) · Nature Reviews Microbiology · doi:10.1038/s41579-020-0382-3 · Cited by 168 · see citing works
Roles of RNA Methylation on Tumor Immunity and Clinical Implications
Zhang, M., Song, J., Yuan, W., Zhang, W., & Sun, Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.641507 · Cited by 162 · see citing works
Regulation of Viral Infection by the RNA Modification N6 -Methyladenosine
Williams, G. D., Gokhale, N. S., & Horner, S. M. (2019) · Annual Review of Virology · doi:10.1146/annurev-virology-092818-015559 · Cited by 157 · see citing works
McIntyre, W., Netzband, R., Bonenfant, G., Biegel, J. M., Miller, C. M., Fuchs, G., Henderson, E., Arra, M., Canki, M., Fabris, D., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky029 · Cited by 152 · see citing works
Granot-Matok, Y., & Peer, D. (2017) · Seminars in Immunology · doi:10.1016/j.smim.2017.08.015 · Cited by 154 · see citing works
Kim, G., Imam, H., Khan, M. A., & Siddiqui, A. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014260 · Cited by 147 · see citing works
Exploiting RIG-I-like receptor pathway for cancer immunotherapy
Jiang, Y., Zhang, H., Wang, J., Chen, J., Guo, Z., Liu, Y., & Hua, H. M. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01405-9 · Cited by 143 · see citing works
Immunogenicity of In Vitro -Transcribed RNA
Mu, X. N., & Hur, S. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00521 · Cited by 138 · see citing works
Synthesis of low immunogenicity RNA with high-temperature in vitro transcription
Wu, M. Z., Asahara, H., Tzertzinis, G., & Roy, B. (2020) · RNA · doi:10.1261/rna.073858.119 · Cited by 135 · see citing works
Guirguis, A. A., Ofir-Rosenfeld, Y., Knezevic, K., Blackaby, W., HARDICK, D. J., Chan, Y.-C., Motazedian, A., Gillespie, A., Vassiliadis, D., Lam, E. Y. N., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0007 · Cited by 137 · see citing works
RNA Modifications Modulate Activation of Innate Toll-Like Receptors
Freund, I., Eigenbrod, T., Helm, M., & Dalpke, A. H. (2019) · Genes · doi:10.3390/genes10020092 · Cited by 119 · see citing works
N6-Methyladenosine RNA Modification in Inflammation: Roles, Mechanisms, and Applications
Luo, J., Xu, T., & Sun, K. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.670711 · Cited by 117 · see citing works
Xue, M., Zhao, B. S., Zhang, Z. S., Lu, M., Harder, O. E., Chen, P., Lu, Z., Li, A., Ma, Y., Xu, Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12504-y · Cited by 111 · see citing works
Circular RNAs in Immune Response and Viral Infection
Yan, L., & Chen, Y. G. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.08.006 · Cited by 110 · see citing works
Exosomes for mRNA delivery: a novel biotherapeutic strategy with hurdles and hope
Aslan, C., Kiaie, S. H., Zolbanin, N. M., Lotfinejad, P., Ramezani, R., Kashanchi, F., & Jafari, R. (2021) · BMC Biotechnology · doi:10.1186/s12896-021-00683-w · Cited by 111 · see citing works
m6A RNA methylation, a new hallmark in virus-host interactions
Brocard, M., Ruggieri, A., & Locker, N. (2017) · Journal of General Virology · doi:10.1099/jgv.0.000910 · Cited by 105 · see citing works
Recent Developments in mRNA-Based Protein Supplementation Therapy to Target Lung Diseases
Sahu, I., Haque, A. K. M. A., Weidensee, B., Weinmann, P., & Kormann, M. S. D. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.02.019 · Cited by 104 · see citing works
Zhao, Y., Chen, Y., JIN, M. L., & Wang, J. (2021) · Theranostics · doi:10.7150/thno.54967 · Cited by 105 · see citing works
Guide RNA modification as a way to improve CRISPR/Cas9-based genome-editing systems
Filippova, J. A., Matveeva, A. M., Zhuravlev, E. S., & Stepanov, G. A. (2019) · Biochimie · doi:10.1016/j.biochi.2019.09.003 · Cited by 95 · see citing works
Chen, S., Kumar, S., Tirumuru, N., Welch, J. L., Hu, L., He, C., Stapleton, J. T., & Wu, L. J. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009421 · Cited by 92 · see citing works
Host-cell interactions in HBV infection and pathogenesis: the emerging role of m6A modification
Kostyusheva, A., Brezgin, S., Glebe, D., Kostyushev, D. S., & Chulanov, V. (2021) · Emerging Microbes & Infections · doi:10.1080/22221751.2021.2006580 · Cited by 90 · see citing works
Synthetic modified messenger RNA for therapeutic applications
Gao, M., Zhang, Q., Feng, X.-H., & Liu, J. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.06.020 · Cited by 89 · see citing works
Gokhale, N. S., & Horner, S. M. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006188 · Cited by 85 · see citing works
Emerging role of RNA modification N6-methyladenosine in immune evasion
Lou, X., Wang, J.-J., Wei, Y., & Sun, J. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03585-z · Cited by 82 · see citing works
mRNA in cancer immunotherapy: beyond a source of antigen
Hoecke, L. V., Verbeke, R., Dewitte, H., Lentacker, I., Vermaelen, K. Y., Breckpot, K., & Lint, S. V. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01329-3 · Cited by 80 · see citing works
Post-transcriptional regulation of antiviral gene expression by N6-methyladenosine
McFadden, M. J., McIntyre, A. B. R., Mourelatos, H. A., Abell, N. S., Gokhale, N. S., Ipas, H., Xhemalçe, B., Mason, C. E., & Horner, S. M. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108798 · Cited by 80 · see citing works
From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies
Adachi, H., Hengesbach, M., Yu, Y., & Morais, P. (2021) · Biomedicines · doi:10.3390/biomedicines9050550 · Cited by 80 · see citing works
mRNA vaccines: the most recent clinical applications of synthetic mRNA
Kwon, S., Kwon, M., Im, S., Lee, K., & Lee, H. (2022) · Archives of Pharmacal Research · doi:10.1007/s12272-022-01381-7 · Cited by 81 · see citing works
Kennedy, E. M., Courtney, D., Tsai, K., & Cullen, B. R. (2017) · Journal of Virology · doi:10.1128/jvi.02263-16 · Cited by 78 · see citing works
Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy
Duan, L.-J., Wang, Q., Zhang, C., Yang, D.-X., & Zhang, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.923647 · Cited by 79 · see citing works
Moradian, H., Roch, T., Anthofer, L., Lendlein, A., & Gossen, M. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.01.004 · Cited by 75 · see citing works
Rivière, L., Bergez, M., Mönch, S., Qu, B., Rieß, M., Vondran, F. W. R., Liese, J., Hornung, V., Urban, S., & König, R. (2020) · Viruses · doi:10.3390/v12060592 · Cited by 68 · see citing works
Epitranscriptomic(N6-methyladenosine) Modification of Viral RNA and Virus-Host Interactions
Imam, H., Kim, G., & Siddiqui, A. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.584283 · Cited by 68 · see citing works
Why U matters: detection and functions of pseudouridine modifications in mRNAs
Rodell, R., Robalin, N., & Martínez, N. M. (2023) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2023.10.008 · Cited by 65 · see citing works
Review of machine learning for lipid nanoparticle formulation and process development
Dorsey, P. J., Lau, C. L., Chang, T., Doerschuk, P. C., & D’Addio, S. M. (2024) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2024.09.015 · Cited by 73 · see citing works
Bernard, M., Bazin, E., Petiot, N., Lemdani, K., Commandeur, S., Verdelet, C., Margot, S., Perkov, V., Ripoll, M., Garinot, M., et al. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.05.004 · Cited by 62 · see citing works
Enabling mRNA Therapeutics: Current Landscape and Challenges in Manufacturing
Youssef, M., Hitti, C., Fulber, J. P. C., & Kamen, A. (2023) · Biomolecules · doi:10.3390/biom13101497 · Cited by 62 · see citing works
Understanding the impact of in vitro transcription byproducts and contaminants
Lenk, R., Kleindienst, W., Szabó, G. T., Baiersdörfer, M., Boros, G., Keller, J. M., Mahiny, A. J., & Vlatkovic, I. (2024) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2024.1426129 · Cited by 63 · see citing works
Host cell-intrinsic innate immune recognition of SARS-CoV-2
Madden, E. A., & Diamond, M. S. (2021) · Current Opinion in Virology · doi:10.1016/j.coviro.2021.11.002 · Cited by 56 · see citing works
Advances of mRNA vaccine in tumor: a maze of opportunities and challenges
Yuan, Y., Gao, F., Chang, Y., Zhao, Q., & He, X. (2023) · Biomarker Research · doi:10.1186/s40364-023-00449-w · Cited by 58 · see citing works
Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome
Kasumba, D. M., & Grandvaux, N. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.12.003 · Cited by 56 · see citing works
TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes
LaRocca, T. J., Mariani, A., Watkins, L. R., & Link, C. D. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104514 · Cited by 56 · see citing works
N6-Methyladenosine Regulates Host Responses to Viral Infection
McFadden, M. J., & Horner, S. M. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.11.008 · Cited by 56 · see citing works
van Dülmen, M., Muthmann, N., & Rentmeister, A. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202100352 · Cited by 54 · see citing works
Lu, M., Xue, M., Wang, H.-T., Kairis, E. L., Ahmad, S., Wei, J., Zhang, Z. S., Liu, Q., Zhang, Y., Gao, Y., et al. (2021) · Journal of Virology · doi:10.1128/jvi.01939-20 · Cited by 53 · see citing works
m6A: Widespread regulatory control in virus replication
Manners, O., Baquero-Pérez, B., & Whitehouse, A. (2018) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2018.10.015 · Cited by 51 · see citing works
Therapeutic mRNA Engineering from Head to Tail
Jia, L., & Qian, S. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00541 · Cited by 51 · see citing works
An Update on mRNA-Based Viral Vaccines
Jeeva, S., Kim, K., Shin, C. H., Wang, B., & Kang, S. (2021) · Vaccines · doi:10.3390/vaccines9090965 · Cited by 49 · see citing works
Post-Transcriptional Regulation of Viral RNA through Epitranscriptional Modification
Courtney, D. (2021) · Cells · doi:10.3390/cells10051129 · Cited by 49 · see citing works
Furuse, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179127 · Cited by 48 · see citing works
Regulation of antiviral innate immunity by chemical modification of viral RNA
Li, N., & Rana, T. M. (2022) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1720 · Cited by 44 · see citing works
Functional sequencing read annotation for high precision microbiome analysis
Zhu, C., Miller, M. J., Marpaka, S., Vaysberg, P., Rühlemann, M. C., Wu, G. G., Heinsen, F., Tempel, M., Zhao, L., Lieb, W., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx1209 · Cited by 48 · see citing works
Potential health risks of mRNA-based vaccine therapy: A hypothesis
Acevedo‐Whitehouse, K. A., & Bruno, R. (2023) · Medical Hypotheses · doi:10.1016/j.mehy.2023.111015 · Cited by 54 · see citing works
Ding, S., Liu, H., Liu, L., Ma, L., Chen, Z., Zhu, M., Liu, L., Zhang, X., Hao, H., Zuo, L., et al. (2024) · Cell Death and Disease · doi:10.1038/s41419-023-06412-9 · Cited by 46 · see citing works
Dávalos, A., Henriques, R., Latasa, M. J., Laparra, M., & Coca, M. A. (2019) · EFSA Supporting Publications · doi:10.2903/sp.efsa.2019.en-1688 · Cited by 47 · see citing works
Ferro, A., Saccu, G., Mattivi, S., Gaido, A., Sanchez, M. B. H., Haque, S., Silengo, L., Altruda, F., Durazzo, M., & Fagoonee, S. (2024) · Biomolecules · doi:10.3390/biom14030277 · Cited by 45 · see citing works
Xue, M., Zhang, Y., Wang, H., Kairis, E. L., Lu, M., Ahmad, S., Attia, Z., Harder, O. E., Zhang, Z. S., Wei, J., et al. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1010142 · Cited by 44 · see citing works
RNA regulatory processes in RNA virus biology
Cross, S. T., Michalski, D., Miller, M. R., & Wilusz, J. (2019) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1536 · Cited by 40 · see citing works
Rajan, K. S., Doniger, T., Cohen‐Chalamish, S., Chen, D., Semo, O., Aryal, S., Saar, E. G., Chikne, V., Gerber, D., Unger, R., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz477 · Cited by 41 · see citing works
Self RNA Sensing by RIG-I–like Receptors in Viral Infection and Sterile Inflammation
Stok, J. E., Quiroz, M. E. V., & van der Veen, A. G. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000488 · Cited by 41 · see citing works
Advances in nucleic acid-based cancer vaccines
Liao, H., & Liu, S. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-024-01102-w · Cited by 45 · see citing works
Stepanov, G. A., Zhuravlev, E. S., Shender, V. О., Nushtaeva, A. A., Balakhonova, E., Mozhaeva, E., Kasakin, M. F., Koval, V. V., Lomzov, A. A., Pavlyukov, M. S., et al. (2018) · Genes · doi:10.3390/genes9110531 · Cited by 40 · see citing works
Emerging gene therapies for cystic fibrosis
Miah, K. M., Hyde, S. C., & Gill, D. R. (2019) · Expert Review of Respiratory Medicine · doi:10.1080/17476348.2019.1634547 · Cited by 39 · see citing works
In Vitro Transcribed RNA-Based Platform Vaccines: Past, Present, and Future
Perenkov, A. D., Sergeeva, A. D., Vedunova, M. V., & Krysko, D. V. (2023) · Vaccines · doi:10.3390/vaccines11101600 · Cited by 40 · see citing works
Chen, J., Wang, C., Fei, W., Fang, X., & Hu, X. (2019) · PubMed Central · Cited by 39 · see citing works
Self-citationThe Emerging Role of RNA Modifications in the Regulation of Antiviral Innate Immunity
Tong, J., Zhang, W., Chen, Y., Yuan, Q., Qin, N.-N., & Qu, G. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.845625 · Cited by 36 · see citing works
How RNA modifications regulate the antiviral response
Thompson, M. G., Sacco, M. T., & Horner, S. M. (2021) · Immunological Reviews · doi:10.1111/imr.13020 · Cited by 36 · see citing works
Tang, L., Wei, X., Li, T., Chen, Y., Dai, Z., Lu, C., & Zheng, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.630358 · Cited by 37 · see citing works
Synthetic circRNA therapeutics: innovations, strategies, and future horizons
Cai, J., Qiu, Z., Cho, W. C. S., Liu, Z., Chen, S., Li, H., Chen, K., Li, Y., Zuo, C., & Qiu, M. (2024) · MedComm · doi:10.1002/mco2.720 · Cited by 38 · see citing works
Kim, G., & Siddiqui, A. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00581-3 · Cited by 36 · see citing works
Nanoformulations targeting immune cells for cancer therapy: mRNA therapeutics
Yang, W., Cao, J., Cheng, H., Chen, L., Yu, M., Chen, Y., & Cui, X. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.11.014 · Cited by 36 · see citing works
RNA Binding Proteins as Pioneer Determinants of Infection: Protective, Proviral, or Both?
Lisy, S. M., Rothamel, K. L., & Ascano, M. (2021) · Viruses · doi:10.3390/v13112172 · Cited by 35 · see citing works
Cytidine Acetylation Yields a Noninflammatory Synthetic Messenger RNA
Nance, K. D., Gamage, S. T., Alam, M. M., Yang, A., Levy, M. J., Link, C. N., Florens, L. A., Washburn, M. P., Gu, S., Oppenheim, J. J., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.07.003 · Cited by 35 · see citing works
m6A reader proteins: the executive factors in modulating viral replication and host immune response
Yang, D., Zhao, G., & Zhang, H. M. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1151069 · Cited by 35 · see citing works
RNA regulatory mechanisms that control antiviral innate immunity
Gokhale, N. S., Smith, J. R., Gelder, R. D. V., & Savan, R. (2021) · Immunological Reviews · doi:10.1111/imr.13019 · Cited by 34 · see citing works
The RNA polymerase III–RIG-I axis in antiviral immunity and inflammation
Naesens, L., Haerynck, F., & Gack, M. U. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.04.002 · Cited by 33 · see citing works
- Authors
- Durbin, A. F., Wang, C., Marcotrigiano, J., & Gehrke, L.
- Affiliations
- Harvard University (US)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Gehrke, Lee
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2016-11-02
- Volume
- 7
- Issue
- 5
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC5030355
- OpenAlex
- W2522303658
- Cited by
- 238
- References
- 58
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 25 · 2023: 27 · 2022: 28 · 2021: 49 · 2020: 30 · 2019: 23 · 2018: 13 · 2017: 8
- FWCI
- 8.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- HHS | U.S. Public Health Service (CA159132, AI100190)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- RIG-I, modified nucleotides, innate immune signaling, pseudouridine, RNA conformational change, RNA therapeutics, immune evasion, viral RNA recognition
- MeSH terms
- DEAD Box Protein 58, Cell Line, Humans, Immunity, Innate, Models, Molecular, Ribonucleosides, RNA, Viral, Signal Transduction, Hepacivirus, Interferon-beta
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
