Cited by 557interferon and immune responsesImmune Response and InflammationRNA regulation and disease

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Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates

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Goubau, Delphine, Schlee, Martin, Deddouche, Safia, Pruijssers, Andrea J., Zillinger, Thomas, Goldeck, Marion, Schuberth, Christine, Van der Veen, Annemarthe G., Fujimura, Tsutomu, Rehwinkel, Jan, Iskarpatyoti, Jason A., Barchet, Winfried, Ludwig, Janos, Dermody, Terence S., Hartmann, Gunther, Reis e Sousa, Caetano·2014·Nature

DOI 10.1038/nature13590PMC PMC4201573

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Abstract

Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.

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Mdkhana, B., Sharif‐Askari, N. S., Ramakrishnan, R. K., Goel, S., Hamid, Q. A., & Halwani, R. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s277716 · Cited by 31
Defective Interfering Genomes and the Full-Length Viral Genome Trigger RIG-I After Infection With Vesicular Stomatitis Virus in a Replication Dependent Manner
Linder, A., Bothe, V., Linder, N., Schwarzlmueller, P., Dahlström, F., Bartenhagen, C., Dugas, M., Pandey, D., Thorn‐Seshold, J., Boehmer, D. F. R., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.595390 · Cited by 31
“We and others have shown that optimal synthetic ligands for RIG-I consist of double-stranded 5’-tri- or 5’-di-phosphorylated RNA (11, 14, 15).”
Background
Induction and Evasion of Type-I Interferon Responses during Influenza A Virus InfectionPreprint
Muñoz-Moreno, R., Martínez‐Romero, C., & García‐Sastre, A. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a038414 · Cited by 34
“Although RIG-I recognizes di- and triphosphate groups located at the end of dsRNA (Hornung et al. 2006; Goubau et al. 2014), MDA5 recognizes and binds to long dsRNAs that are potentially IAV replicative intermediates as well as web-like RNA aggregates with no end specificity (Kato et al. 2006;…”
Background
IFIH1 (MDA5) is required for innate immune detection of intron-containing RNA expressed from the HIV-1 provirus
Guney, M. H., Nagalekshmi, K., McCauley, S. M., Carbone, C., Aydemir, Ö., & Luban, J. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2404349121 · Cited by 28
PARP1 depletion induces RIG-I-dependent signaling in human cancer cells
Ghosh, R., Roy, S., & Franco, S. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194611 · Cited by 30
“Among RNA sensors, RIG-I senses dsRNAs with 5’-triphosphorylated (5’-PPP) or 5’-diphosphorylated (5’-PP) structures [44, 45] and, once activated, forms a complex with MAVS at the outer mitochondrial membrane to trigger signaling cascades that induce IFNs [46].”
Synthesis and Translation of Viral mRNA in Reovirus-Infected Cells: Progress and Remaining Questions
Lemay, G. (2018) · Viruses · doi:10.3390/v10120671 · Cited by 30
“Further work then indicated that oncogenic Ras can also inhibit interferon induction through negative regulation of RIG-I signaling involved in activation of the interferon response in the presence of viral RNA [198].”
BackgroundInfluential
Targeting intrinsic RIG-I signaling turns melanoma cells into type I interferon-releasing cellular antitumor vaccines
Bek, S., Stritzke, F., Wintges, A., Nedelko, T., Böhmer, D. F. R., Fischer, J. C., Haas, T. L., Poeck, H., & Heidegger, S. M. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1570779 · Cited by 30
Unzippers, Resolvers and Sensors: A Structural and Functional Biochemistry Tale of RNA Helicases
Leitão, A. L., Costa, M. C., & Enguita, F. J. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16022269 · Cited by 31
“Recently, Goubau and coworkers [92] showed that RIG-I also mediates antiviral responses to RNAs bearing terminal 5'-diphosphates (5'-pp).”
Background
Nuclear innate sensors for nucleic acids in immunity and inflammation
Lin, H., & Cao, X. (2020) · Immunological Reviews · doi:10.1111/imr.12893 · Cited by 29
Functional Characterization of the Cnidarian Antiviral Immune Response Reveals Ancestral Complexity
Lewandowska, M., Sharoni, T., Admoni, Y., Aharoni, R., & Moran, Y. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab197 · Cited by 29
MDA5 disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA
Yu, Q., del Valle, A. H., Singh, R., & Modis, Y. (2021) · Nature Communications · doi:10.1038/s41467-021-27062-5 · Cited by 30
Regulation and mechanisms of action of RNA helicases
Lang, N., Jagtap, P. K. A., & Hennig, J. (2024) · RNA Biology · doi:10.1080/15476286.2024.2415801 · Cited by 29
“As part of the RIG-I like helicase family, RIG-I is a well-known immune receptor which detects viral genomic RNA carrying a 5’-diphosphate or triphosphate moiety [87–89].”
Signaling through RIG-I and type I interferon receptor: Immune activation by Newcastle disease virus in man versus immune evasion by Ebola virus (Review)
Schirrmacher, V. (2015) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2015.2213 · Cited by 28
“RIG has the structural combination of an N-terminal caspase recruitment domain (CARD) not and a C-terminal RNA helicase domain with which it interacts with the viral non-capped RNA (25).”
Virus Sensor RIG-I Represses RNA Interference by Interacting with TRBP through LGP2 in Mammalian Cells
Takahashi, T., Nakano, Y., Onomoto, K., Yoneyama, M., & Ui‐Tei, K. (2018) · Genes · doi:10.3390/genes9100511 · Cited by 28
Links between recognition and degradation of cytoplasmic viral RNA in innate immune response
Oshiumi, H., Mifsud, E. J., & Daito, T. (2015) · Reviews in Medical Virology · doi:10.1002/rmv.1865 · Cited by 29
Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach
Olukitibi, T. A., Ao, Z., Mahmoudi, M., Kobinger, G., & Yao, X. (2019) · Microorganisms · doi:10.3390/microorganisms7100402 · Cited by 27
“The RLRs are also host PRRs which are involved in the regulation of innate immune responses by recognizing the pathogen-specific 5′ di or triphosphate non-self RNA in bacteria and viruses, consequently leading to the transcription of IFN-β [64,65].”
Background
RIG-I Recognition of RNA Targets: The Influence of Terminal Base Pair Sequence and Overhangs on Affinity and Signaling
Ren, X., Linehan, M. M., Iwasaki, A., & Pyle, A. M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.052 · Cited by 27
Recognition of Reovirus RNAs by the Innate Immune System
Abad, A. T., & Danthi, P. (2020) · Viruses · doi:10.3390/v12060667 · Cited by 27
“The different size classes of reovirus genome segments differ in their ability to interact with RIG-I and MDA-5, indicating that these sensors have a preference for particular sizes of dsRNA [22,32].”
BackgroundInfluential
A loosened gating mechanism of RIG-I leads to autoimmune disorders
Lei, Y., Fei, P., Song, B., Shi, W., Luo, C., Luo, D., Li, D., Chen, W., & Zheng, J. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac361 · Cited by 27
“Intriguingly, this latch motif exhibited an EX1 kinetic regime that displays bimodal isotope clusters associated with RIG-IE510V and RIG-IQ517H but not RIG-I or CARDs (1-228) (Figure 1D).”
Background
MAVI1, an endoplasmic reticulum–localized microprotein, suppresses antiviral innate immune response by targeting MAVS on mitochondrion
Shi, T.-T., Huang, Y., Li, Y., Dai, X., He, Y., Ding, J.-C., Ran, T., Shi, Y., Yuan, Q., Li, W.-J., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg7053 · Cited by 29
RIG-I recognizes metabolite-capped RNAs as signaling ligands
Schweibenz, B., Solotchi, M., Hanpude, P., Devarkar, S. C., & Patel, S. S. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad518 · Cited by 26
“This data was fit to equations (2) and (3) o estimate the IC 50 value rather than K D .”
Method
The TAR-RNA binding protein is required for immunoresponses triggered by Cardiovirus infection
Komuro, A., Homma, Y., Negoro, T., Barber, G. N., & Horvath, C. M. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.10.023 · Cited by 26
p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice
Yi, Y., Jian, J., González-Gugel, E., Shi, Y., Tian, Q., Fu, W., Hettinghouse, A., Song, W., Liu, R., He, M., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.02.012 · Cited by 26
“r the CC BY-N and sensor proteins (Akira et al., 2001; Iwasaki and Medzhitov, 2004; Gay et al., 2014; Goubau et al., 2014).”
Background
CARMA3 Is a Host Factor Regulating the Balance of Inflammatory and Antiviral Responses against Viral Infection
Jiang, C., Zhou, Z., Quan, Y., Zhang, S., Wang, T., Zhao, X., Morrison, C. R., Heise, M. T., He, W., Miller, M. S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.031 · Cited by 25
Cytoplasm and Beyond: Dynamic Innate Immune Sensing of Influenza A Virus by RIG-I
Liu, G., & Zhou, Y. (2019) · Journal of Virology · doi:10.1128/jvi.02299-18 · Cited by 25
SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development
Nguyen, T. A., Bieging-Rolett, K. T., Putoczki, T. L., Wicks, I. P., Attardi, L. D., & Pang, K. C. (2019) · iScience · doi:10.1016/j.isci.2019.09.009 · Cited by 25
Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN–Mediated Innate Immune Responses to Influenza A Virus Infection
Vijayan, M., Xia, C., Song, Y. E., Ngo, H., Studstill, C. J., Drews, K., Fox, T. E., Johnson, M. C., Hiscott, J. B., KESTER, M. A., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601959 · Cited by 27
RIG-I–like Receptor Regulation of Immune Cell Function and Therapeutic Implications
Solstad, A., Hogaboam, O., Forero, A., & Hemann, E. A. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2200395 · Cited by 25
Structural Variability in the RLR-MAVS Pathway and Sensitive Detection of Viral RNAs
Jiang, Q. (2018) · Medicinal Chemistry · doi:10.2174/1573406415666181219101613 · Cited by 25
LGP2 virus sensor enhances apoptosis by upregulating apoptosis regulatory genes through TRBP-bound miRNAs during viral infection
Takahashi, T., Nakano, Y., Onomoto, K., Yoneyama, M., & Ui‐Tei, K. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1143 · Cited by 24
Viperin_sv1 promotes RIG-I expression and suppresses SVCV replication through its radical SAM domain
Gao, Y., Li, C., Shi, L., Wang, F., Ye, J., Lu, Y., & Liu, X. (2021) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2021.104166 · Cited by 23
Chikungunya virus nonstructural protein 1 is a versatile RNA capping and decapping enzyme
Law, M. C. Y., Zhang, K., Tan, Y. B., Nguyen, T. M., & Luo, D. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105415 · Cited by 23
“We discovered that nsP1 possesses a novel decapping activity to remove mGp cap from various sources including short capped RNA and cellular mRNAs, where the resulting mRNAs bearing the 5 0 end diphosphates in turn will activate RIG-I – mediated immune response (15).”
Background
Influenza Virus—Host Co-evolution. A Predator-Prey Relationship?
Voskarides, K., Christaki, E., & Nikolopoulos, G. K. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02017 · Cited by 23
Transient kinetic studies of the antiviral Drosophila Dicer-2 reveal roles of ATP in self–nonself discrimination
Singh, P., Jonely, M., Leslie, E., Rejali, N. A., Noriega, R., & Bass, B. (2021) · eLife · doi:10.7554/elife.65810 · Cited by 23
“The founding member of the RLR helicase family, mammalian RIG-I, recognizes di- and triphosphates on the blunt termini of viral dsRNA to distinguish this nonself species from self-transcripts, which are capped or monophosphorylated (Goubau et al., 2014; Schlee, 2013).”
Background
Structural insights into the distinctive RNA recognition and therapeutic potentials of RIG‐I‐like receptors
Batool, M., Kim, M. S., & Choi, S. (2021) · Medicinal Research Reviews · doi:10.1002/med.21845 · Cited by 23
“I CTD, tilted by 20° to bring it closer to the ligand.39 In MDA5, CTD also interacts with the Hel1 to wrap around the dsRNA.39 This conformation assists in the filament formation that leads to oligomerization with the MAVS CARDs, F IGURE 2 Pairwise sequence alignment of RLR domains.”
BackgroundInfluential
NUDT2 initiates viral RNA degradation by removal of 5′-phosphates
Laudenbach, B. T., Krey, K., Emslander, Q., Andersen, L. L., Reim, A., Scaturro, P., Mundigl, S., Dächert, C., Manske, K., Moser, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27239-y · Cited by 23
Self-assembling short immunostimulatory duplex RNAs with broad-spectrum antiviral activity
Si, L., Bai, H., Oh, C. Y., Jiang, A. R., Hong, F., Zhang, T., Ye, A. Y., Jordan, T. X., Logue, J., McGrath, M. E., et al. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.08.031 · Cited by 23
Synthesis of 5′-NAD-Capped RNA
Höfer, K., Abele, F., Schlotthauer, J., & Jäschke, A. (2016) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6b00072 · Cited by 23
A comprehensive study on cellular RNA editing activity in response to infections with different subtypes of influenza a viruses
Cao, Y., Cao, R., Huang, Y., Zhou, H., Liu, Y., Li, X., Wu, Z., & Hao, P. (2018) · BMC Genomics · doi:10.1186/s12864-017-4330-1 · Cited by 24
The catcher in the RIG-I
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Combating viral contaminants in CHO cells by engineering innate immunity
Chiang, A. W. T., Li, S., Kellman, B. P., Chattopadhyay, G., Zhang, Y., Kuo, C., Gutierrez, J. M., Ghazi, F., Schmeisser, H., Ménard, P., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-45126-x · Cited by 23

Authors: Goubau, D., Schlee, M., Deddouche, S., Pruijssers, A. J., Zillinger, T., Goldeck, M., Schuberth, C., Van der Veen, A. G., Fujimura, T., Rehwinkel, J., Iskarpatyoti, J. A., Barchet, W., Ludwig, J., Dermody, T. S., Hartmann, G., & Reis e Sousa, C.
Affiliations: Cancer Research UK (GB)
University Hospital Bonn (DE)
Vanderbilt University (US)
Consejo Superior de Investigaciones Científicas (ES)
Corresponding author: Goubau, Delphine
ORCID: Schlee, Martin
Pruijssers, Andrea J.
Zillinger, Thomas
Goldeck, Marion
Fujimura, Tsutomu
Rehwinkel, Jan
Barchet, Winfried
Dermody, Terence S.
Hartmann, Gunther
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2014-08-10
Volume: 514
Issue: 7522
Pages: 372-375
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature13590
PMC: PMC4201573
OpenAlex: W2156869719
Cited by: 557
References: 36
Citations by year: 2026: 16 · 2025: 40 · 2024: 43 · 2023: 34 · 2022: 54 · 2021: 56 · 2020: 51 · 2019: 51 · 2018: 62 · 2017: 44 · 2016: 43 · 2015: 55 · 2014: 8
FWCI: 22.85
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders: Cancer Research UK (15689, A3598)
National Institute of Allergy and Infectious Diseases (R01AI038296, R37AI038296, R01AI050800)
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, antiviral innate immunity, RIG-I-like receptors, MDA5, MAVS, type I interferon, reovirus, L-A virus, viral RNA recognition, self/non-self discrimination, cytosolic RNA sensing, RNA-dependent protein kinase, interferon-stimulated genes, interferon lambda
MeSH terms: DEAD Box Protein 58, Animals, Base Sequence, Female, Immunity, Innate, Male, Diphosphates, Reoviridae, RNA, Viral, Genome, Viral, Base Pairing, Mice, DEAD-box RNA Helicases

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Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates

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