Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L
Open accessAbstract
The interferon-induced enzymes 2'-5'-oligoadenylate synthetase (OAS) and RNase L are key components of innate immunity involved in sensory and effector functions following viral infections. Upon binding target RNA, OAS is activated to produce 2'-5'-linked oligoadenylates (2-5A) that activate RNase L, which then cleaves single-stranded self and non-self RNA. Modified nucleosides that are present in cellular transcripts have been shown to suppress activation of several RNA sensors. Here, we demonstrate that in vitro transcribed, unmodified RNA activates OAS, induces RNase L-mediated ribosomal RNA (rRNA) cleavage and is rapidly cleaved by RNase L. In contrast, RNA containing modified nucleosides activates OAS less efficiently and induces limited rRNA cleavage. Nucleoside modifications also make RNA resistant to cleavage by RNase L. Examining translation in RNase L(-/-) cells and mice confirmed that RNase L activity reduces translation of unmodified mRNA, which is not observed with modified mRNA. Additionally, mRNA containing the nucleoside modification pseudouridine is translated longer and has an extended half-life. The observation that modified nucleosides in RNA reduce 2-5A pathway activation joins OAS and RNase L to the list of RNA sensors and effectors whose functions are limited when RNA is modified, confirming the role of nucleoside modifications in suppressing immune recognition of RNA.
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Pseudouridine-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 [21]
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 [21]
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 [175]
These alterations possibly lead to a blunted specific immune response.
“These alterations possibly lead to a blunted specific immune response.37,133, 134, 135”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [135]
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- Authors
- Anderson, B. R., Muramatsu, H., Jha, B. K., Silverman, R. H., Weissman, D., & Kariko, K.
- Affiliations
- University of Pennsylvania (US)
- Cleveland Clinic (US)
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-08-03
- Volume
- 39
- Issue
- 21
- Pages
- 9329-9338
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3241635
- OpenAlex
- W2071136305
- Cited by
- 356
- References
- 54
- Citations by year
- 2026: 30 · 2025: 40 · 2024: 39 · 2023: 49 · 2022: 43 · 2021: 51 · 2020: 19 · 2019: 17 · 2018: 14 · 2017: 13 · 2016: 6 · 2015: 12 · 2014: 6 · 2013: 7 · 2012: 9
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (T32 GM- 07229)
- National Heart, Lung, and Blood Institute (R42HL087688, R42HL87688)
- National Cancer Institute (R01CA044059)
- National Institute of General Medical Sciences (T32GM007229, T32GM07229)
- National Institute of Allergy and Infectious Diseases (R01 AI50484, R01AI050484)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007748, T32 DK-07748)
- National Institute of Neurological Disorders and Stroke (R01NS029331)
- National Institute of Dental and Craniofacial Research (R21DE019059)
- National Center for Research Resources (T32RR007063)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- nucleoside modification, RNA, 2',5'-oligoadenylate synthetase, RNase L, pseudouridine, mRNA translation, mRNA stability, RNA sensors, innate immunity, interferon signaling, viral RNA sensing, immune evasion
- MeSH terms
- Animals, Cells, Cultured, Endoribonucleases, Half-Life, Humans, Nucleosides, Pseudouridine, RNA, RNA, Ribosomal, Protein Biosynthesis, Uridine, 2',5'-Oligoadenylate Synthetase, Mice
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