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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Background
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van der Veen, A. G., Maillard, P. V., Schmidt, J. M., Lee, S. A., Deddouche, S., Borg, A., Kjær, S., Snijders, A. P., & Sousa, C. R. E. (2018) · The EMBO Journal · doi:10.15252/embj.201797479 · Cited by 135
“Whilst RIG-I recognises 5 0 di-or tri-phosphates at the base-paired extremities of viral RNA, MDA5 and LGP2 recognise long double-stranded RNA (dsRNA), the precise features of which are less well-defined (Hornung et al , 2006; Kato et al , 2006; Pichlmair et al , 2006, 2009; Goubau et al , 2014).”
Infection with a Brazilian isolate of Zika virus generates RIG‐I stimulatory RNA and the viral NS5 protein blocks type I IFN induction and signaling
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Cross-priming in cancer immunology and immunotherapy
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Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway
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“Initial recognition of viral RNA by RIG-I occurs at a tri- or diphosphorylated blunt end of the viral RNA (Cui et al., 2008; Goubau et al., 2014; Hornung et al., 2006; Jiang and Chen, 2011; Kowalinski et al., 2011; Luo et al., 2011; Pichlmair et al., 2006).”
Background
Past, Present and Future of Oncolytic Reovirus
Müller, L. M. E., Berkeley, R. A., Barr, T., Ilett, E. J., & Errington‐Mais, F. (2020) · Cancers · doi:10.3390/cancers12113219 · Cited by 130
Slicing and dicing viruses: antiviral RNA interference in mammals
Maillard, P. V., van der Veen, A. G., Poirier, E. Z., & Sousa, C. R. E. (2019) · The EMBO Journal · doi:10.15252/embj.2018100941 · Cited by 128
“…0 PP/5 0 PPP) at its 5 0 extremity (Hornung et al, 2006; Pichlmair et al, 2006; Schlee et al, 2009; Schmidt et al, 2009; Goubau et al, 2014), such as found in the genomes of influenza virus, Sendai virus and reovirus (Baum et al, 2010; Rehwinkel et al, 2010; Weber et al, 2013; Goubau et al, 2014).”
Mitochondria-localised ZNFX1 functions as a dsRNA sensor to initiate antiviral responses through MAVS
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LGP2 synergy with MDA5 in RLR-mediated RNA recognition and antiviral signaling
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“Like the 5′-PPP generated by viral polymerases, recognition of 5′-PP dsRNA serves to discriminate self from non-self as 5′-PP RNAs are found in some viruses, such as the reovirus genome, but are not found in uninfected cells (Goubau et al., 2014).”
Background
Biomedical applications of mRNA nanomedicine
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“RIG-I binds 50 tri- and diphosphates present on short double stranded (ds) RNA whereas MDA5 binds long dsRNA molecules (Hornung et al., 2006; Pichlmair et al., 2006; Goubau et al., 2014; Kato et al., 2008, 2006; Gitlin et al., 2006; Wang et al., 2010; Lu et al., 2010; Luo et al., 2011).”
Background
mRNA therapeutics deliver a hopeful message
Zhong, Z., Cafferty, S. M., Combes, F., Huysmans, H., Temmerman, J. D., Gitsels, A., Vanrompay, D. C. G., Catani, J. P., & Sanders, N. N. (2018) · Nano Today · doi:10.1016/j.nantod.2018.10.005 · Cited by 124
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In vitro–transcribed guide RNAs trigger an innate immune response via the RIG-I pathway
Wienert, B., Shin, J. J., Zelin, E., Pestal, K., & Corn, J. E. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005840 · Cited by 117
Dicer uses distinct modules for recognizing dsRNA termini
Sinha, N. K., Iwasa, J., Shen, P. S., & Bass, B. (2017) · Science · doi:10.1126/science.aaq0921 · Cited by 115
The Multiples Fates of the Flavivirus RNA Genome During Pathogenesis
Mazeaud, C., Freppel, W., & Chatel‐Chaix, L. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00595 · Cited by 120
“It is a cytosolic PRR that targets specifically dsRNA and the 5 tri/diphosphate moiety of short structured uncapped RNAs (Yoneyama et al., 2004; Pichlmair et al., 2006; Takahasi et al., 2008; Goubau et al., 2014) .”
Background
Influenza A Virus Panhandle Structure Is Directly Involved in RIG-I Activation and Interferon Induction
Liu, G., Park, H.-S., Pyo, H., Liu, Q., & Zhou, Y. (2015) · Journal of Virology · doi:10.1128/jvi.00232-15 · Cited by 114
Potential role for snoRNAs in PKR activation during metabolic stress
Youssef, O. A., Safran, S. A., Nakamura, T., Nix, D. A., Hotamışlıgil, G. S., & Bass, B. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1424044112 · Cited by 113
“Interestingly, RIG-I, a dsRNA-sensing protein, is activated by RNA with either a 5′-triphosphate or a 5′-diphosphate (35).”
Background
mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles and beyond
Sentí, M. E., del Valle, L. G., & Schiffelers, R. M. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115190 · Cited by 124
LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways
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The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways
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RIG-I-Like Receptor-Mediated Recognition of Viral Genomic RNA of Severe Acute Respiratory Syndrome Coronavirus-2 and Viral Escape From the Host Innate Immune Responses
Kouwaki, T., Nishimura, T., Wang, G., & Oshiumi, H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.700926 · Cited by 113
“MDA5 recognizes long dsRNA and makes a nucleoprotein filament along the dsRNA, whereas RIG-I binds shorter dsRNA and requires tri or diphosphate at the 5′ end (2, 37, 38).”
Background
Physiological functions of RIG-I-like receptors
Yoneyama, M., Kato, H., & Fujita, T. (2024) · Immunity · doi:10.1016/j.immuni.2024.03.003 · Cited by 117
A minimal RNA ligand for potent RIG-I activation in living mice
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“Recent studies indicate that RNAs bearing a diphosphate at the 5′ terminus are bona fide ligands for RIG-I (33).”
Background
Non-immunotherapy application of LNP-mRNA: Maximizing efficacy and safety
Vlatkovic, I. (2021) · Biomedicines · doi:10.3390/biomedicines9050530 · Cited by 112
“RIG-I is a RLR that recognize 5′ppp dsRNA and 5′pp dsRNA [37].”
Background
Type I Interferons Modulate CD8 + T Cell Immunity to mRNA Vaccines
Beuckelaer, A. D., Grooten, J., & Koker, S. D. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.01.006 · Cited by 110
From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape
Chakraborty, C., Sharma, A. R., Bhattacharya, M., & Lee, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.679344 · Cited by 114
Molecular basis for specific viral RNA recognition and 2′-O-ribose methylation by the dengue virus nonstructural protein 5 (NS5)
Zhao, Y., Soh, T. S., Lim, S. P., Chung, K. Y., Swaminathan, K., Vasudevan, S. G., Shi, P., Lescar, J., & Luo, D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514978112 · Cited by 109
Intracellular detection of viral nucleic acids
Sparrer, K. M. J., & Gack, M. U. (2015) · Current Opinion in Microbiology · doi:10.1016/j.mib.2015.03.001 · Cited by 105
Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases
Okude, H., Ori, D., & Kawai, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.625833 · Cited by 104
“Although short dsRNA without a 5′-triphosphate was proposed to activate RIG-I, a 5′-tri- or 5′-di-phosphate end in dsRNA seems to be important for the strong activation of RIG-I (61, 62).”
Background
Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation
Li, P., Kaiser, P. D., Lampiris, H. W., Kim, P., Yukl, S. A., Havlir, D. V., Greene, W. C., & Wong, J. K. (2016) · Nature Medicine · doi:10.1038/nm.4124 · Cited by 105
Innate Immune Sensing of Influenza A Virus
Malik, G., & Zhou, Y. (2020) · Viruses · doi:10.3390/v12070755 · Cited by 114
Regulation of RIG-I Activation by K63-Linked Polyubiquitination
Okamoto, M., Kouwaki, T., Fukushima, Y., & Oshiumi, H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01942 · Cited by 100
“RIG-I is a cytoplasmic RNA helicase and a PRR that recognizes cytoplasmic 5′ tri-or diphosphate double-stranded RNA (dsRNA) (3) (4) (5) .”
Background
Cryo-EM Structures of MDA5-dsRNA Filaments at Different Stages of ATP Hydrolysis
Yu, Q., Qu, K., & Modis, Y. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.012 · Cited by 101
“However, the CTDs of RIG-I and LGP2 bind dsRNA blunt ends, with 50-di- or triphosphate caps and unphosphorylated, respectively, and both proteins have a much lower propensity than MDA5 to form filaments (Devarkar et al., 2016; Goubau et al., 2014; Luo et al., 2012).”
Background
Review: Cell Death, Nucleic Acids, and Immunity
Elkon, K. B. (2018) · Arthritis & Rheumatology · doi:10.1002/art.40452 · Cited by 99
Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment
Elion, D. L., & Cook, R. S. (2018) · Oncotarget · doi:10.18632/oncotarget.25626 · Cited by 99
ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA
Lässig, C., Matheisl, S., Sparrer, K. M. J., Mann, C. C. D. O., Moldt, M., Patel, J. R., Goldeck, M., Hartmann, G., García‐Sastre, A., Hornung, V., et al. (2015) · eLife · doi:10.7554/elife.10859 · Cited by 96
“ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5’ triphosphate dsRNA.”
Background

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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