@article{MTMT:32039148,
	title = {Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation},
	url = {https://m2.mtmt.hu/api/publication/32039148},
	author = {Anderson, Bart R. and Muramatsu, Hiromi and Nallagatla, Subba R. and Bevilacqua, Philip C. and Sansing, Lauren H. and Weissman, Drew and Karikó, Katalin},
	doi = {10.1093/nar/gkq347},
	journal-iso = {NUCLEIC ACIDS RES},
	journal = {NUCLEIC ACIDS RESEARCH},
	volume = {38},
	unique-id = {32039148},
	issn = {0305-1048},
	abstract = {Previous studies have shown that the translation level of in vitro transcribed messenger RNA (mRNA) is enhanced when its uridines are replaced with pseudouridines; however, the reason for this enhancement has not been identified. Here, we demonstrate that in vitro transcripts containing uridine activate RNA-dependent protein kinase (PKR), which then phosphorylates translation initiation factor 2-alpha (eIF-2 alpha), and inhibits translation. In contrast, in vitro transcribed mRNAs containing pseudouridine activate PKR to a lesser degree, and translation of pseudouridine-containing mRNAs is not repressed. RNA pull-down assays demonstrate that mRNA containing uridine is bound by PKR more efficiently than mRNA with pseudouridine. Finally, the role of PKR is validated by showing that pseudouridine- and uridine-containing RNAs were translated equally in PKR knockout cells. These results indicate that the enhanced translation of mRNAs containing pseudouridine, compared to those containing uridine, is mediated by decreased activation of PKR.},
	keywords = {INHIBITION; Toll-Like Receptors; DOUBLE-STRANDED-RNA; THERMAL-STABILITY; Binding domain; PROTEIN-KINASE PKR; interferon induction; 2',5'-OLIGO(A) POLYMERASE; TREATED HELA-CELLS},
	year = {2010},
	eissn = {1362-4962},
	pages = {5884-5892},
	orcid-numbers = {Bevilacqua, Philip C./0000-0001-8074-3434; Sansing, Lauren H./0000-0002-6898-1680; Karikó, Katalin/0000-0002-1864-3851}
}

@article{MTMT:32039151,
	title = {Incorporation of Pseudouridine Into mRNA Yields Superior Nonimmunogenic Vector With Increased Translational Capacity and Biological Stability},
	url = {https://m2.mtmt.hu/api/publication/32039151},
	author = {Karikó, Katalin and Muramatsu, Hiromi and Welsh, Frank A. and Ludwig, Janos and Kato, Hiroki and Akira, Shizuo and Weissman, Drew},
	doi = {10.1038/mt.2008.200},
	journal-iso = {MOL THER},
	journal = {MOLECULAR THERAPY},
	volume = {16},
	unique-id = {32039151},
	issn = {1525-0016},
	abstract = {In vitro-transcribed mRNAs encoding physiologically important proteins have considerable potential for therapeutic applications. However, in its present form, mRNA is unfeasible for clinical use because of its labile and immunogenic nature. Here, we investigated whether incorporation of naturally modified nucleotides into transcripts would confer enhanced biological properties to mRNA. We found that mRNAs containing pseudouridines have a higher translational capacity than unmodified mRNAs when tested in mammalian cells and lysates or administered intravenously into mice at 0.015-0.15 mg/kg doses. The delivered mRNA and the encoded protein could be detected in the spleen at 1, 4, and 24 hours after the injection, where both products were at significantly higher levels when pseudouridine-containing mRNA was administered. Even at higher doses, only the unmodified mRNA was immunogenic, inducing high serum levels of interferon-alpha ( IFN-alpha). These findings indicate that nucleoside modification is an effective approach to enhance stability and translational capacity of mRNA while diminishing its immunogenicity in vivo. Improved properties conferred by pseudouridine make such mRNA a promising tool for both gene replacement and vaccination.},
	keywords = {ACTIVATION; RECOGNITION; DENDRITIC CELLS; Therapy; DOUBLE-STRANDED-RNA; plasmid DNA; GENE-TRANSFER; TOLL-LIKE RECEPTOR-3; RIG-I; Biotechnology & Applied Microbiology; Genetics & Heredity},
	year = {2008},
	eissn = {1525-0024},
	pages = {1833-1840},
	orcid-numbers = {Karikó, Katalin/0000-0002-1864-3851}
}

@article{MTMT:32039262,
	title = {Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA},
	url = {https://m2.mtmt.hu/api/publication/32039262},
	author = {Karikó, Katalin and Buckstein, M. and Ni, H. and Weissman, D.},
	doi = {10.1016/j.immuni.2005.06.008},
	journal-iso = {IMMUNITY},
	journal = {IMMUNITY},
	volume = {23},
	unique-id = {32039262},
	issn = {1074-7613},
	abstract = {DNA and RNA stimulate the mammalian innate immune system through activation of Toll-like receptors (TLRs). DNA containing methylated CpG motifs, however, is not stimulatory. Selected nucleosides in naturally occurring RNA are also methylated or otherwise modified, but the immunomodulatory effects of these alterations remain untested. We show that RNA signals through human TLR3, TLR7, and TLR8, but incorporation of modified nucleosides m5C, m6A, m5U, s2U, or pseudouridine ablates activity. Dendritic cells (DCs) exposed to such modified RNA express significantly less cytokines and activation markers than those treated with unmodified RNA. DCs and TLR-expressing cells are potently activated by bacterial and mitochondrial RNA, but not by mammalian total RNA, which is abundant in modified nucleosides. We conclude that nucleoside modifications suppress the potential of RNA to activate DCs. The innate immune system may therefore detect RNA lacking nucleoside modification as a means of selectively responding to bacteria or necrotic tissue. Copyright ©2005 by Elsevier Inc.},
	keywords = {Humans; DENDRITIC CELLS; ARTICLE; signal transduction; signal transduction; RNA; RNA; Toll-Like Receptors; Cytokines; toll like receptor; human; nucleotide sequence; priority journal; controlled study; Evolution, Molecular; DNA determination; enzyme activity; enzyme activation; MOLECULAR RECOGNITION; Cell Line; Biological Markers; gene activation; human cell; HLA-DR Antigens; Antigens, CD; Phosphatidylethanolamines; nucleosides; Membrane Glycoproteins; Immunoglobulins; Receptors, Cell Surface; rna transcription; Toll-like receptor 3; Toll-Like Receptor 7; Toll-like receptor 8},
	year = {2005},
	eissn = {1097-4180},
	pages = {165-175},
	orcid-numbers = {Karikó, Katalin/0000-0002-1864-3851}
}

@article{MTMT:32039266,
	title = {mRNA Is an Endogenous Ligand for Toll-like Receptor 3},
	url = {https://m2.mtmt.hu/api/publication/32039266},
	author = {Karikó, Katalin and Ni, H. and Capodici, J. and Lamphier, M. and Weissman, D.},
	doi = {10.1074/jbc.M310175200},
	journal-iso = {J BIOL CHEM},
	journal = {JOURNAL OF BIOLOGICAL CHEMISTRY},
	volume = {279},
	unique-id = {32039266},
	issn = {0021-9258},
	abstract = {Toll-like receptors (TLRs) are the basic signaling receptors of the innate immune system. They are activated by molecules associated with pathogens or injured host cells and tissue. TLR3 has been shown to respond to double stranded (ds) RNA, a replication intermediary for many viruses. Here we present evidence that heterologous RNA released from or associated with necrotic cells or generated by in vitro transcription also stimulates TLR3 and induces immune activation. To assess RNA-mediated TLR3 activation, human embryonic kidney 293 cells stably expressing TLR3 and containing a nuclear factor-κB-dependent luciferase reporter were generated. Exposing these cells to in vitro transcribed RNA resulted in a TLR3-dependent induction of luciferase activity and interleukin-8 secretion. Treatment with in vitro transcribed mRNA activated nuclear factor-κB via TLR3 through a process that was dose-dependent and involved tyrosine phosphorylation. Furthermore, in vitro transcribed natural or 2′-fluoro-substituted mRNA induced the expression of TLR3, interferon regulatory factor-1, tumor necrosis factor-α, and interleukin-1 receptor-associated kinase-M mRNA in human dendritic cells (DCs). DCs responded to mRNA treatment by expressing activation markers, and this maturation was inhibited by antagonistic TLR3-specific antibody. Endogenous RNA released from or associated with necrotic cells also stimulated DCs, leading to interferon-α secretion, which could be abolished by pretreatment of necrotic cells with RNase. These results demonstrate that RNA, likely through secondary structure, is a potent host-derived activator of TLR3. This finding has potential physiologic relevance because RNA escaping from damaged tissue or contained within endocytosed cells could serve as an endogenous ligand for TLR3 that induces or otherwise modulates immune responses.},
	keywords = {Humans; LIGAND; NECROSIS; DENDRITIC CELLS; ARTICLE; LIGANDS; signal transduction; RNA; RNA; PROTEIN SECONDARY STRUCTURE; Tumor necrosis factor-alpha; Toll-Like Receptors; immunology; human; Up-Regulation; Enzyme-Linked Immunosorbent Assay; priority journal; controlled study; GENISTEIN; Dose-Response Relationship, Drug; nonhuman; animal cell; Animalia; protein phosphorylation; Enzyme Inhibitors; immune system; Plasmids; Nucleic Acid Conformation; Blotting, Northern; Transfection; Cell Line; Transcription, Genetic; human cell; T lymphocyte activation; Tumor Necrosis Factor; RNA, Messenger; messenger rna; host resistance; immune response; tyrosine; VIRUSES; PATHOGENS; BIOCHEMISTRY; NF-kappa B; immunoglobulin enhancer binding protein; protein kinases; Staurosporine; Membrane Glycoproteins; Dendritic cell; transcription regulation; antigen presenting cell; enzyme kinetics; interleukin 1; Receptors, Cell Surface; Luciferases; luciferase; Interleukin-8; RNA, Double-Stranded; Biological organs; messenger rna synthesis; RNA replication; interleukin 1 receptor; toll like receptor 3; Interleukin-1 Receptor-Associated Kinases; Toll-like receptor 3; immune systems},
	year = {2004},
	eissn = {1083-351X},
	pages = {12542-12550},
	orcid-numbers = {Karikó, Katalin/0000-0002-1864-3851}
}