Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation
Open accessAbstract
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-2α), 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.
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Substitution of chemically modified nucleotides in mRNA enhances stability and transfection capability and decreases immunogenicity.
“Substitution of chemically modified nucleotides in messenger ribonucleic acid (mRNA) enhances stability and transfection capability, and decreases immunogenicity1–3”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [3]
The Discussion says modified nucleosides reduce host-defense responses, supporting decreased immunogenicity. The Introduction describes mRNA transfection as efficient, and the Results show increased translation from pseudouridine-containing mRNA, but neither establishes that substitution improves transfection capability. The paper’s References name a study of increased biological stability; the cited paper’s own discussion and results do not establish that stability claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNative RNA activates pattern recognition receptors such as toll-like receptors and triggers type I interferon production, resulting in translational shutoff and systemic inflammation.
“Native RNA activates pattern recognition receptors such as toll-like receptors and triggers type I interferon (IFN) production, resulting in translational shutoff and systemic inflammation3.”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [3]
The Introduction states that RNA can activate innate immune receptors, including Toll-like receptors, and that RNA-activated PKR represses translation. The Discussion likewise links PKR activation to translational inhibition. Our copy does not establish the claimed sequence of type I interferon production leading to translational shutoff or systemic inflammation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIncorporation of naturally occurring nucleosides and stringent purification to remove double-stranded RNA contaminants can circumvent the high innate immunogenicity of purified unmodified IVT mRNA.
“This can be circumvented by the incorporation of naturally occurring nucleosides and by applying stringent purification to remove double-stranded RNA contaminants (19–21).”
From mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model (2022) · cites this paper as [21]
The Discussion (page not provided) says that naturally occurring nucleoside modifications reduce PKR activation and that modified mRNA can have low immunogenicity. The mRNA synthesis methods describe precipitation and washing, but neither they nor the retrieved passages say that stringent purification removes double-stranded RNA contaminants or that such removal circumvents immunogenicity. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPseudouridine-containing mRNAs reduced activation of known RNA sensors substantially.
“Transferring this concept to in vitro transcribed mRNA, for instance, pseudouridine-containing mRNAs reduced activation of known RNA sensors substantially.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [22]
The Results (‘Conventional in vitro transcribed mRNA activates PKR’) show that pseudouridine-containing mRNA activates the RNA sensor PKR less than unmodified mRNA. The Introduction says pseudouridine-modified RNA can avoid activation of other receptors, including TLRs and RIG-I, but this paper does not establish a substantial reduction across multiple sensors specifically for pseudouridine-containing mRNAs. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe two uridine analogs pseudouridine (Ψ) or 1-methyl-pseudouridine (m1Ψ) are widely used for mRNA therapeutics because they can increase mRNA stability and help modulate the host immune response.
“The two uridine analogs pseudouridine (Ψ) or 1-methyl-pseudouridine (m1Ψ) are widely used for mRNA therapeutics because they can increase mRNA stability and help modulate the host immune response31,32.”
From Human 5′ UTR design and variant effect prediction from a massively parallel translation assay (2019) · cites this paper as [32]
The Introduction and Discussion (page numbers unavailable) support pseudouridine’s role in reducing innate immune activation and its potential for therapeutic mRNA delivery. They do not establish that either analog increases mRNA stability, and the paper does not address 1-methyl-pseudouridine or establish that both analogs are widely used in therapeutics. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Pseudouridine-containing mRNAs were still translated and produced even more protein compared to unmodified mRNA.
“Although pseudouridine is primarily found in tRNA, rRNA, and small nuclear RNAs, pseudouridine-containing mRNAs were still translated and produced even more protein compared to unmodified mRNA.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [22]
Nucleoside modifications are well known to limit or even inhibit RNA sensor engagement.
“In addition, nucleoside modifications are well known to limit or even inhibit RNA sensor engagement.20,21,22”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [22]
Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS); additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.
“Nucleoside-modified mRNA can reduce the activation of TLRs, retinoic acid-inducible gene I (RIG-I), protein kinase R (PKR), and 2′-5′-oligoadenylate synthetase (OAS). Additionally, nucleoside modification increases translation activity and resistance against RNase L-mediated degradation.54,81,173–176”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [174]
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- Authors
- Anderson, B. R., Muramatsu, H., Nallagatla, S. R., Bevilacqua, P. C., Sansing, L. H., Weissman, D., & Karikó, K.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- Karikó, Katalin
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05-10
- Volume
- 38
- Issue
- 17
- Pages
- 5884-5892
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC2943593
- OpenAlex
- W2156788486
- Cited by
- 682
- References
- 60
- Citations by year
- 2026: 67 · 2025: 99 · 2024: 143 · 2023: 90 · 2022: 77 · 2021: 52 · 2020: 22 · 2019: 22 · 2018: 26 · 2017: 17 · 2016: 21 · 2015: 13 · 2014: 6 · 2013: 12 · 2012: 8
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Cleveland Clinic
- Cleveland Clinic Foundation
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R42HL087688)
- National Institute of General Medical Sciences (T32GM007229, R01GM058709)
- National Institute of Allergy and Infectious Diseases (R01AI050484)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007748)
- National Institute of Dental and Craniofacial Research (R21DE019059)
- National Center for Research Resources (T32RR007063)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- pseudouridine, mRNA translation, PKR, RNA-dependent protein kinase, eIF2α phosphorylation, translation initiation, uridine, in vitro transcribed mRNA, RNA-protein interactions
- MeSH terms
- Animals, Cell Line, Cells, Cultured, Humans, Pseudouridine, RNA, Messenger, Protein Biosynthesis, eIF-2 Kinase, Mice
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