5'-Triphosphate RNA Is the Ligand for RIG-I
Abstract
The structural basis for the distinction of viral RNA from abundant self RNA in the cytoplasm of virally infected cells is largely unknown. We demonstrated that the 5′-triphosphate end of RNA generated by viral polymerases is responsible for retinoic acid–inducible protein I (RIG-I)–mediated detection of RNA molecules. Detection of 5′-triphosphate RNA is abrogated by capping of the 5′-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-α response in a phosphatase-sensitive manner. 5′-triphosphate RNA directly binds to RIG-I. Thus, uncapped 5′-triphosphate RNA (now termed 3pRNA) present in viruses known to be recognized by RIG-I, but absent in viruses known to be detected by MDA-5 such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIG-I.
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Several RNA structural features are immunostimulatory due to interactions with RNA sensors such as Toll-like receptors, RIG-I, and PKR.
“However, several RNA structural features have been described as immunostimulatory due to interactions with various RNA sensors such as Toll-like receptors, RIG-I, and PKR.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [10]
ψ and m1ψ substitutions for U have been widely adopted for mRNA therapeutics and vaccines due to improved in-cell translation and better control of innate immune responses.
“In particular, we focused on ψ and m1ψ, since these substitutions for U have been widely adopted for mRNA therapeutics and vaccines due to improved in-cell translation and to better control of innate immune responses2,3,8,67 through avoidance of recognition by cellular toll-like receptors (TLR7 and TLR8)68, RIG‑I, and PKR69–71.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [71]
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 [54]
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- Authors
- Hornung, V., Ellegast, J., Kim, S., Brzózka, K., Jung, A., Kato, H., Poeck, H., Akira, S., Conzelmann, K.-K., Schlee, M., Endres, S., & Hartmann, G.
- Affiliations
- University of Bonn (DE)
- Division of Clinical Pharmacology, Department of Internal Medicine, University of Munich, 80336 Munich, Germany.
- Corresponding author
- Hartmann, Gunther
- ORCID
- Venue
- Science
- Published
- 2006-11-10
- Volume
- 314
- Issue
- 5801
- Pages
- 994-997
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2017515700
- Cited by
- 2,474
- References
- 19
- Citations by year
- 2026: 66 · 2025: 88 · 2024: 105 · 2023: 83 · 2022: 108 · 2021: 122 · 2020: 115 · 2019: 127 · 2018: 104 · 2017: 94 · 2016: 103 · 2015: 117 · 2014: 148 · 2013: 153 · 2012: 143
- FWCI
- 58.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- 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, 5'-triphosphate RNA, RNA sensing, antiviral innate immunity, interferon-alpha, viral RNA detection, RNA capping, MDA5, negative-strand RNA viruses, picornavirus
- MeSH terms
- DEAD Box Protein 58, Animals, Cell Line, Cells, Cultured, Cytosol, Humans, Ligands, Monocytes, Oligoribonucleotides, Phosphates, Phosphorylation, Rabies virus, Receptors, Immunologic, RNA, RNA Caps, DNA-Directed RNA Polymerases, RNA, Double-Stranded, RNA, Viral, Transcription, Genetic, Transfection, Viral Proteins, Virus Replication, Interferon-alpha, Interferon-beta, Mice, DEAD-box RNA Helicases
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