Cited by 356interferon and immune responsesRNA regulation and diseaseRNA modifications and cancer

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Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L

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Anderson, B. R., Muramatsu, H., Jha, B. K., Silverman, R. H., Weissman, D., Kariko, K.·2011·Nucleic Acids Research

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Abstract

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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Authors: Anderson, B. R., Muramatsu, H., Jha, B. K., Silverman, R. H., Weissman, D., & Kariko, K.
Affiliations: University of Pennsylvania (US)
Cleveland Clinic (US)
ORCID: Anderson, B. R.
Muramatsu, H.
Jha, B. K.
Silverman, R. H.
Weissman, D.
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
DOI: 10.1093/nar/gkr586
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: cc-by-nc
creativecommons.org/licenses/by-nc/3.0 (vor, 1889 d)
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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Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L

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