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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“Cytosolic retinoic acid inducible gene I (RIG-I)-like helicases (RLH) are a family of nucleic acid-sensing pattern recognition receptors that can be activated to induce pro-inflammatory cytokine production, ASC (apoptosis-associated speck-like protein containing a carboxy-terminal CARD)-dependent inflammasome activati…”
Background
Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5
Louber, J., Brunel, J., Uchikawa, E., Cusack, S., & Gerlier, D. (2015) · BMC Biology · doi:10.1186/s12915-015-0166-9 · Cited by 54
“They recognize RNA species harboring 5′-triphosphate or diphosphate ends and/or double-stranded features (dsRNA) [3–7] that are physiologically absent from the cytosol (see [2] for review).”
Filament assemblies in foreign nucleic acid sensors
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Adenosine-to-Inosine RNA Editing in Health and Disease
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“( B) ADAR1 edits long dsRNAs located in the cytoplasm, suppressing the downstream recognition by MDA5 or RIG-1.”
Influential
Role of pyroptosis in cancer and its therapeutic regulation
Mamun, A. A., Mimi, A. A., Aziz, M. A., Zaeem, M., Ahmed, T., Munir, F., & Xiao, J. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174444 · Cited by 53
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“postulated, a 59-diphosphate (Goubau et al., 2014), but such RNA species are not normally present in mamma-”
Background
The Innate Immune Signalling Pathways: Turning RIG-I Sensor Activation against Cancer
Iurescia, S., Fioretti, D., & Rinaldi, M. (2020) · Cancers · doi:10.3390/cancers12113158 · Cited by 55
“RIG-I binds to short, uncapped blunt double-strand (ds) RNA duplex molecules bearing a triphosphate (3P) [37,38] and diphosphate (2P) groups at their 5′ end [39] or to RNA containing self-complementary 3′ and 5′ ends, which pair to form a secondary structure called “pan-handles” [37].”
Background
Type I interferonopathies—an expanding disease spectrum of immunodysregulation
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PACT- and RIG-I-Dependent Activation of Type I Interferon Production by a Defective Interfering RNA Derived from Measles Virus Vaccine
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Background
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“possess capped positive-sense RNAs (60).”
BackgroundInfluential
LGP2 virus sensor regulates gene expression network mediated by TRBP-bound microRNAs
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“RIG-I recognizes relatively short duplexed regions of RNA with blunt-ended 5’-triphosphate or 5’-diphosphate, which are often present at the end of the genomic RNAs of (+) ssRNA viruses (Hornung et al., 2006; Goubau et al., 2014).”
Background
Stimulating Innate Immunity to Enhance Radiation Therapy–Induced Tumor Control
Baird, J. R., Monjazeb, A. M., Shah, O., McGee, H. M., Murphy, W. J., Crittenden, M. R., & Gough, M. J. (2017) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2017.04.014 · Cited by 51
Recent Advances and Contradictions in the Study of the Individual Roles of Ubiquitin Ligases That Regulate RIG-I-Like Receptor-Mediated Antiviral Innate Immune Responses
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SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA
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The Antiviral and Antitumor Effects of Defective Interfering Particles/Genomes and Their Mechanisms
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“RIG-I recognition of RNAs with 5-triphosphates or 5-diphosphates effectively augments the production of IFNs (Goubau et al., 2014), A DI RNA containing both 5-triphosphates and an intermediatelength of the double-stranded region found in the measles virus is the perfect agonists for RIG-I.”
Background
Camouflage and interception: how pathogens evade detection by intracellular nucleic acid sensors
Unterholzner, L., & Almine, J. F. (2018) · Immunology · doi:10.1111/imm.13030 · Cited by 48
An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response
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The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection
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Oncolytic Reovirus Inhibits Immunosuppressive Activity of Myeloid-Derived Suppressor Cells in a TLR3-Dependent Manner
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USP14 promotes K63‐linked RIG‐I deubiquitination and suppresses antiviral immune responses
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Structural Insights into Mitochondrial Antiviral Signaling Protein (MAVS)-Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Signaling
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“RIG-I specifically recognizes 5 -triphosphates and 5 -diphosphates of viral dsRNA via its C-terminal domain (3, 4).”
Background
Long noncoding RNAs: Novel regulators of virus‐host interactions
Liu, S., Liu, X., Li, J., Zhou, H., Carr, M. J., Zhang, Z., & Shi, W. (2019) · Reviews in Medical Virology · doi:10.1002/rmv.2046 · Cited by 47
“Virus infection can also activate retinoic acid‐inducible gene‐I (RIG‐I), Toll‐like receptors (TLRs), melanoma differentiation‐associated gene 5 (MDA5), and Nod‐like receptor (NLR) pathways,(70) which in turn activate interferon regulatory factors, such as IRF3, IRF7, and the major proinflammatory transcription factor…”
Background
Know Thyself: RIG-I-Like Receptor Sensing of DNA Virus Infection
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The Functional Deubiquitinating Enzymes in Control of Innate Antiviral Immunity
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A rapid RIG-I signaling relay mediates efficient antiviral response
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Protect this house: cytosolic sensing of viruses
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RIG-I Detects Kaposi’s Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner
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Zebrafish prmt7 negatively regulates antiviral responses by suppressing the retinoic acid‐inducible gene‐I‐like receptor signaling
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“21,37,38 As shown in Figure 9B,C, compared to the WT prmt7, and prmt7 (374-R) that completely lost their suppressive role on RLR signaling, prmt7(1-373) still inhibited RLR signaling, suggesting that the N-terminal domain of prmt7 is essential for the role of prmt7 in suppressing RLR signaling.”
MethodResult
The crosstalk between viral RNA- and DNA-sensing mechanisms
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Viral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis
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The mitochondrial protein ERAL1 suppresses RNA virus infection by facilitating RIG-I-like receptor signaling
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Shaping the Innate Immune Response Through Post-Transcriptional Regulation of Gene Expression Mediated by RNA-Binding Proteins
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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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