Immune Signaling by RIG-I-like Receptors
2011; Cell Press; Volume: 34; Issue: 5 Linguagem: Inglês
10.1016/j.immuni.2011.05.003
ISSN1097-4180
Autores Tópico(s)Cytokine Signaling Pathways and Interactions
ResumoThe RIG-I-like receptors (RLRs) RIG-I, MDA5, and LGP2 play a major role in pathogen sensing of RNA virus infection to initiate and modulate antiviral immunity. The RLRs detect viral RNA ligands or processed self RNA in the cytoplasm to trigger innate immunity and inflammation and to impart gene expression that serves to control infection. Importantly, RLRs cooperate in signaling crosstalk networks with Toll-like receptors and other factors to impart innate immunity and to modulate the adaptive immune response. RLR regulation occurs at a variety of levels ranging from autoregulation to ligand and cofactor interactions and posttranslational modifications. Abberant RLR signaling or dysregulation of RLR expression is now implicated in the development of autoimmune diseases. Understanding the processes of RLR signaling and response will provide insights to guide RLR-targeted therapeutics for antiviral and immune-modifying applications. The RIG-I-like receptors (RLRs) RIG-I, MDA5, and LGP2 play a major role in pathogen sensing of RNA virus infection to initiate and modulate antiviral immunity. The RLRs detect viral RNA ligands or processed self RNA in the cytoplasm to trigger innate immunity and inflammation and to impart gene expression that serves to control infection. Importantly, RLRs cooperate in signaling crosstalk networks with Toll-like receptors and other factors to impart innate immunity and to modulate the adaptive immune response. RLR regulation occurs at a variety of levels ranging from autoregulation to ligand and cofactor interactions and posttranslational modifications. Abberant RLR signaling or dysregulation of RLR expression is now implicated in the development of autoimmune diseases. Understanding the processes of RLR signaling and response will provide insights to guide RLR-targeted therapeutics for antiviral and immune-modifying applications. RIG-I like receptors (RLRs) are a family of DExD/H box RNA helicases that function as cytoplasmic sensors of pathogen-associated molecular patterns (PAMPs) within viral RNA. The RLRs signal downstream transcription factor activation to drive type 1 interferon (IFN) production and antiviral gene expression that elicits an intracellular immune response to control virus infection. To date, three RLR members have been identified: RIG-I (retinoic acid-inducible gene I), which is the founding member and therefore best characterized of this family, MDA5 (melanoma differentiation associated factor 5), and LGP2 (laboratory of genetics and physiology 2 and a homolog of mouse D11lgp2). The three RLRs are broadly expressed in most tissues where they signal innate immune activation in a variety of cell types. Although they play a prominent role in triggering innate defenses within myeloid cells, epithelial cells, and cells of the central nervous system, their actions are not essential for IFN production in plasmacytoid dendritic cells despite their expression in this cell type. RLR expression is typically maintained at low levels in resting cells but is greatly increased with IFN exposure and after virus infection (Kang et al., 2004Kang D.C. Gopalkrishnan R.V. Lin L. Randolph A. Valerie K. Pestka S. Fisher P.B. Expression analysis and genomic characterization of human melanoma differentiation associated gene-5, mda-5: a novel type I interferon-responsive apoptosis-inducing gene.Oncogene. 2004; 23: 1789-1800Crossref PubMed Scopus (95) Google Scholar, Yoneyama et al., 2004Yoneyama M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (1748) Google Scholar, Yoneyama et al., 2005Yoneyama M. Kikuchi M. Matsumoto K. Imaizumi T. Miyagishi M. Taira K. Foy E. Loo Y.M. Gale Jr., M. Akira S. et al.Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.J. Immunol. 2005; 175: 2851-2858PubMed Google Scholar). Further, MDA5 expression was shown to be virus inducible in cells lacking the IFN receptor, suggesting that RLR expression can be driven by a direct virus-inducible signal (Yount et al., 2007Yount J.S. Moran T.M. López C.B. Cytokine-independent upregulation of MDA5 in viral infection.J. Virol. 2007; 81: 7316-7319Crossref PubMed Scopus (22) Google Scholar). The priming of cells with IFN or ectopic expression of the RLRs dramatically sensitizes them for PAMP recognition and immune signaling (Yoneyama et al., 2004Yoneyama M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (1748) Google Scholar, Yoneyama et al., 2005Yoneyama M. Kikuchi M. Matsumoto K. Imaizumi T. Miyagishi M. Taira K. Foy E. Loo Y.M. Gale Jr., M. Akira S. et al.Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.J. Immunol. 2005; 175: 2851-2858PubMed Google Scholar, Sumpter et al., 2005Sumpter Jr., R. Loo Y.M. Foy E. Li K. Yoneyama M. Fujita T. Lemon S.M. Gale Jr., M. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I.J. Virol. 2005; 79: 2689-2699Crossref PubMed Scopus (417) Google Scholar), suggesting that RLR function is in part regulated by their respective expression. Consistent with this idea, pluripotent cells noted to have attenuated interferon response to cytoplasmic RNA PAMPs express little or no RLRs, thus rendering them refractory to cytoplasmic PAMP detection and signaling (Chen et al., 2010Chen L.L. Yang L. Carmichael G.G. Molecular basis for an attenuated cytoplasmic dsRNA response in human embryonic stem cells.Cell Cycle. 2010; 9: 3552-3564Crossref PubMed Scopus (12) Google Scholar). RIG-I and MDA5 detect a variety of viruses and signal the production of IFN and induction of an antiviral response. They share a number of structural similarities (Figure 1) including their organization into three distinct domains: (1) an N-terminal region consisting of tandem caspase activation and recruitment domains (CARD), (2) a central DExD/H box RNA helicase domain with the capacity to hydrolyze ATP and to bind and possibly unwind RNA, and (3) a C-terminal repressor domain (RD) embedded within the C-terminal domain (CTD) that in the case of RIG-I is involved in autoregulation (Yoneyama et al., 2004Yoneyama M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (1748) Google Scholar, Yoneyama et al., 2005Yoneyama M. Kikuchi M. Matsumoto K. Imaizumi T. Miyagishi M. Taira K. Foy E. Loo Y.M. Gale Jr., M. Akira S. et al.Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.J. Immunol. 2005; 175: 2851-2858PubMed Google Scholar, Saito et al., 2007Saito T. Hirai R. Loo Y.M. Owen D. Johnson C.L. Sinha S.C. Akira S. Fujita T. Gale Jr., M. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2.Proc. Natl. Acad. Sci. USA. 2007; 104: 582-587Crossref PubMed Scopus (268) Google Scholar). Although similarly organized, LGP2 lacks the N-terminal CARDs and is currently thought to function as a regulator of RIG-I and MDA5 signaling (Yoneyama et al., 2005Yoneyama M. Kikuchi M. Matsumoto K. Imaizumi T. Miyagishi M. Taira K. Foy E. Loo Y.M. Gale Jr., M. Akira S. et al.Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.J. Immunol. 2005; 175: 2851-2858PubMed Google Scholar). Members of the RLR family have been implicated in the recognition of a variety of viruses, and a list of these viruses is summarized in Table 1. Various studies have shown that RIG-I confers recognition of the hepaciviruses and members of the Paramyxoviridae, Rhabdoviridae, and Orthomyxoviridae virus genera, whereas MDA5 is associated with the detection of members of the Picornaviridae (Kato et al., 2006Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature. 2006; 441: 101-105Crossref PubMed Scopus (1290) Google Scholar). Thus, mice lacking either RIG-I or MDA5 become highly susceptible to RNA virus infection (Kato et al., 2006Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature. 2006; 441: 101-105Crossref PubMed Scopus (1290) Google Scholar, Venkataraman et al., 2007Venkataraman T. Valdes M. Elsby R. Kakuta S. Caceres G. Saijo S. Iwakura Y. Barber G.N. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses.J. Immunol. 2007; 178: 6444-6455PubMed Google Scholar, Satoh et al., 2010Satoh T. Kato H. Kumagai Y. Yoneyama M. Sato S. Matsushita K. Tsujimura T. Fujita T. Akira S. Takeuchi O. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses.Proc. Natl. Acad. Sci. USA. 2010; 107: 1512-1517Crossref PubMed Scopus (166) Google Scholar). In contrast, a subset of viruses including dengue virus, West Nile virus, and reovirus present PAMPs that are recognized during acute infection by both MDA5 and RIG-I (Fredericksen et al., 2008Fredericksen B.L. Keller B.C. Fornek J. Katze M.G. Gale Jr., M. Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1.J. Virol. 2008; 82: 609-616Crossref PubMed Scopus (111) Google Scholar, Loo et al., 2008Loo Y.M. Fornek J. Crochet N. Bajwa G. Perwitasari O. Martinez-Sobrido L. Akira S. Gill M.A. García-Sastre A. Katze M.G. Gale Jr., M. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.J. Virol. 2008; 82: 335-345Crossref PubMed Scopus (328) Google Scholar). Moreover, MDA5 has recently been implicated in the recognition of murine norovirus (McCartney et al., 2008McCartney S.A. Thackray L.B. Gitlin L. Gilfillan S. Virgin H.W. Colonna M. MDA-5 recognition of a murine norovirus.PLoS Pathog. 2008; 4: e1000108Crossref PubMed Scopus (61) Google Scholar). Although LGP2 possesses the ability to bind RNA, it has yet to be shown to be involved in the actual detection of viral RNA during infection (Yoneyama et al., 2005Yoneyama M. Kikuchi M. Matsumoto K. Imaizumi T. Miyagishi M. Taira K. Foy E. Loo Y.M. Gale Jr., M. Akira S. et al.Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.J. Immunol. 2005; 175: 2851-2858PubMed Google Scholar).Table 1RLR Detection of Viral Genera and Viral RNA Genome TypeViruses Detected by RIG-IParamyxoviridae (−) ssRNA, NS Sendai virusKato et al., 2005Kato H. Sato S. Yoneyama M. Yamamoto M. Uematsu S. Matsui K. Tsujimura T. Takeda K. Fujita T. Takeuchi O. Akira S. Cell type-specific involvement of RIG-I in antiviral response.Immunity. 2005; 23: 19-28Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, Yoneyama et al., 2005Yoneyama M. Kikuchi M. Matsumoto K. Imaizumi T. Miyagishi M. Taira K. Foy E. Loo Y.M. Gale Jr., M. Akira S. et al.Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.J. Immunol. 2005; 175: 2851-2858PubMed Google Scholar Newcastle disease virusKato et al., 2005Kato H. Sato S. Yoneyama M. Yamamoto M. Uematsu S. Matsui K. Tsujimura T. Takeda K. Fujita T. Takeuchi O. Akira S. Cell type-specific involvement of RIG-I in antiviral response.Immunity. 2005; 23: 19-28Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar respiratory syncytial virusLoo et al., 2008Loo Y.M. Fornek J. Crochet N. Bajwa G. Perwitasari O. Martinez-Sobrido L. Akira S. Gill M.A. García-Sastre A. Katze M.G. Gale Jr., M. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.J. Virol. 2008; 82: 335-345Crossref PubMed Scopus (328) Google Scholar measlesPlumet et al., 2007Plumet S. Herschke F. Bourhis J.M. Valentin H. Longhi S. Gerlier D. Cytosolic 5′-triphosphate ended viral leader transcript of measles virus as activator of the RIG I-mediated interferon response.PLoS ONE. 2007; 2: e279Crossref PubMed Scopus (88) Google Scholar NipahHabjan et al., 2008Habjan M. Andersson I. Klingström J. Schümann M. Martin A. Zimmermann P. Wagner V. Pichlmair A. Schneider U. Mühlberger E. et al.Processing of genome 5′ termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction.PLoS ONE. 2008; 3: e2032Crossref PubMed Scopus (122) Google Scholar human parainfluenza 5 mRNALuthra et al., 2011Luthra P. Sun D. Silverman R.H. He B. Activation of IFN-β; expression by a viral mRNA through RNase L and MDA5.Proc. Natl. Acad. Sci. USA. 2011; 108: 2118-2123Crossref PubMed Scopus (21) Google ScholarRhabdoviridae (−) ssRNA, NS vesicular stomatitis virusKato et al., 2005Kato H. Sato S. Yoneyama M. Yamamoto M. Uematsu S. Matsui K. Tsujimura T. Takeda K. Fujita T. Takeuchi O. Akira S. Cell type-specific involvement of RIG-I in antiviral response.Immunity. 2005; 23: 19-28Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, Yoneyama et al., 2005Yoneyama M. Kikuchi M. Matsumoto K. Imaizumi T. Miyagishi M. Taira K. Foy E. Loo Y.M. Gale Jr., M. Akira S. et al.Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.J. Immunol. 2005; 175: 2851-2858PubMed Google Scholar rabies virusHornung et al., 2006Hornung V. Ellegast J. Kim S. Brzózka K. Jung A. Kato H. Poeck H. Akira S. Conzelmann K.K. Schlee M. et al.5′-Triphosphate RNA is the ligand for RIG-I.Science. 2006; 314: 994-997Crossref PubMed Scopus (935) Google ScholarOrthomyxoviridae (−) ssRNA NS influenza AKato et al., 2006Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature. 2006; 441: 101-105Crossref PubMed Scopus (1290) Google Scholar influenza BLoo et al., 2008Loo Y.M. Fornek J. Crochet N. Bajwa G. Perwitasari O. Martinez-Sobrido L. Akira S. Gill M.A. García-Sastre A. Katze M.G. Gale Jr., M. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.J. 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Sinha S.C. Akira S. Fujita T. Gale Jr., M. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2.Proc. Natl. Acad. Sci. USA. 2007; 104: 582-587Crossref PubMed Scopus (268) Google ScholarCoronaviridae (+) ssRNA NS murine hepatitis virusRoth-Cross et al., 2008Roth-Cross J.K. Bender S.J. Weiss S.R. Murine coronavirus mouse hepatitis virus is recognized by MDA5 and induces type I interferon in brain macrophages/microglia.J. Virol. 2008; 82: 9829-9838Crossref PubMed Scopus (54) Google ScholarCaliciviridae (+) ssRNA NS murine norovirus-1McCartney et al., 2008McCartney S.A. Thackray L.B. Gitlin L. Gilfillan S. Virgin H.W. Colonna M. MDA-5 recognition of a murine norovirus.PLoS Pathog. 2008; 4: e1000108Crossref PubMed Scopus (61) Google ScholarDNA viruses Epstein-Barr virus EBERSamanta et al., 2006Samanta M. Iwakiri D. Kanda T. Imaizumi T. Takada K. 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Jung A. Kawai T. Ishii K.J. et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature. 2006; 441: 101-105Crossref PubMed Scopus (1290) Google Scholar Theiler's virusKato et al., 2006Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature. 2006; 441: 101-105Crossref PubMed Scopus (1290) Google Scholar Mengo virusKato et al., 2006Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature. 2006; 441: 101-105Crossref PubMed Scopus (1290) Google ScholarDNA viruses vaccinia virusPichlmair et al., 2009Pichlmair A. Schulz O. Tan C.P. Rehwinkel J. Kato H. Takeuchi O. Akira S. Way M. Schiavo G. Reis e Sousa C. Activation of MDA5 requires higher-order RNA structures generated during virus infection.J. Virol. 2009; 83: 10761-10769Crossref PubMed Scopus (117) Google ScholarFlaviviruses Detected by Both MDA5 and RIG-IFlaviviridae Japanese encephalitis virus(Kato et al., 2006Kato H. Takeuchi O. Sato S. Yoneyama M. Yamamoto M. Matsui K. Uematsu S. Jung A. Kawai T. Ishii K.J. et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature. 2006; 441: 101-105Crossref PubMed Scopus (1290) Google Scholar) dengue virus(Loo et al., 2008Loo Y.M. Fornek J. Crochet N. Bajwa G. Perwitasari O. Martinez-Sobrido L. Akira S. Gill M.A. García-Sastre A. Katze M.G. Gale Jr., M. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.J. Virol. 2008; 82: 335-345Crossref PubMed Scopus (328) Google Scholar) West Nile virus(Fredericksen et al., 2008Fredericksen B.L. Keller B.C. Fornek J. Katze M.G. Gale Jr., M. Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1.J. Virol. 2008; 82: 609-616Crossref PubMed Scopus (111) Google Scholar)Reoviridae dsRNA S reovirusKato et al., 2008Kato H. Takeuchi O. Mikamo-Satoh E. Hirai R. Kawai T. Matsushita K. Hiiragi A. Dermody T.S. Fujita T. Akira S. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.J. Exp. Med. 2008; 205: 1601-1610Crossref PubMed Scopus (448) Google Scholar, Loo et al., 2008Loo Y.M. Fornek J. Crochet N. Bajwa G. Perwitasari O. Martinez-Sobrido L. Akira S. Gill M.A. García-Sastre A. Katze M.G. Gale Jr., M. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity.J. Virol. 2008; 82: 335-345Crossref PubMed Scopus (328) Google ScholarAnnotations regarding the virus genome include the nucleotide composition, e.g., single-stranded (ssRNA) or double-stranded RNA (dsRNA); positive (+) or negative (–) sense genomic orientation, and segmentation (S) versus nonsegmentation (NS). Open table in a new tab Annotations regarding the virus genome include the nucleotide composition, e.g., single-stranded (ssRNA) or double-stranded RNA (dsRNA); positive (+) or negative (–) sense genomic orientation, and segmentation (S) versus nonsegmentation (NS). RIG-I was initially characterized as a dsRNA-binding protein that triggered IFN induction and virus signaling in response to the synthetic dsRNA poly(I:C) (Yoneyama et al., 2004Yoneyama M. Kikuchi M. Natsukawa T. Shinobu N. Imaizumi T. Miyagishi M. Taira K. Akira S. Fujita T. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.Nat. Immunol. 2004; 5: 730-737Crossref PubMed Scopus (1748) Google Scholar) and was then identified as a major factor controlling cell permissiveness for hepatitis C virus replication (Sumpter et al., 2005Sumpter Jr., R. Loo Y.M. Foy E. Li K. Yoneyama M. Fujita T. Lemon S.M. Gale Jr., M. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I.J. Virol. 2005; 79: 2689-2699Crossref PubMed Scopus (417) Google Scholar). Several studies have since led to the characterization of molecular features involved in the activation of RIG-I-dependent signaling (further reviewed by Schlee and Hartmann, 2010Schlee M. Hartmann G. The chase for the RIG-I ligand—recent advances.Mol. Ther. 2010; 18: 1254-1262Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). RIG-I preferentially recognizes RNA sequences marked with 5′ triphosphorylated (5′ppp) ends, which serve in part to define a non-self RNA PAMP (Hornung et al., 2006Hornung V. Ellegast J. Kim S. Brzózka K. Jung A. Kato H. Poeck H. Akira S. Conzelmann K.K. Schlee M. et al.5′-Triphosphate RNA is the ligand for RIG-I.Science. 2006; 314: 994-997Crossref PubMed Scopus (935) Google Scholar). Removal of the 5′ppp completely from a PAMP RNA abrogates signaling, whereas diphosphate or monophosphate modifications of the 5′ppp severely attenuate signaling (Hornung et al., 2006Hornung V. Ellegast J. Kim S. Brzózka K. Jung A. Kato H. Poeck H. Akira S. Conzelmann K.K. Schlee M. et al.5′-Triphosphate RNA is the ligand for RIG-I.Science. 2006; 314: 994-997Crossref PubMed Scopus (935) Google Scholar, Kim et al., 2008Kim M.J. Hwang S.Y. Imaizumi T. Yoo J.Y. Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation.J. Virol. 2008; 82: 1474-1483Crossref PubMed Scopus (78) Google Scholar). Studies based on the influenza virus genomic RNA led to the conclusion that independent of length, at least one phosphate at the 5′ end of the RNA is required to trigger RIG-I-dependent signaling but the 5′ppp is required for full signaling potential by RIG-I (Pichlmair et al., 2006Pichlmair A. Schulz O. Tan C.P. Näslund T.I. Liljeström P. Weber F. Reis e Sousa C. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates.Science. 2006; 314: 997-1001Crossref PubMed Scopus (803) Google Scholar). Next-generation sequencing of RNA derived from RIG-I-bound RNA complexes isolated from influenza virus-infected cells confirm that RIG-I associates preferentially with short 5′ppp-RNA sequence motifs along RNA containing some dsRNA regions (Baum et al., 2010Baum A. Sachidanandam R. García-Sastre A. Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing.Proc. Natl. Acad. Sci. USA. 2010; 107: 16303-16308Crossref PubMed Scopus (90) Google Scholar). Comparison of RIG-I and MDA5 interaction with synthetic dsRNA poly(I:C) suggests that whereas MDA5 preferentially recognizes high-molecular-weight poly(I:C) fragments, RIG-I shows a preference for shorter RNA fragments and can also bind to ssRNA (Kato et al., 2008Kato H. Takeuchi O. Mikamo-Satoh E. Hirai R. Kawai T. Matsushita K. Hiiragi A. Dermody T.S. Fujita T. Akira S. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.J. Exp. Med. 2008; 205: 1601-1610Crossref PubMed Scopus (448) Google Scholar). Consistent with these observations, Marques et al., 2006Marques J.T. Devosse T. Wang D. Zamanian-Daryoush M. Serbinowski P. Hartmann R. Fujita T. Behlke M.A. Williams B.R. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells.Nat. Biotechnol. 2006; 24: 559-565Crossref PubMed Scopus (244) Google Scholar reported that blunt-end dsRNA fragments as short as 23 bp can trigger RIG-I-dependent signaling and that RIG-I has a preference for recognizing blunt-ended dsRNA over those with 5′ or 3′ overhangs. Moreover, because ssRNA predicted to impose limited or no secondary structure but containing 5′ppp can also serve as a potent PAMP ligand of RIG-I, it is likely that RIG-I can interact with various RNA substrates based on the presence of a 5′ppp marking the RNA as potential non-self PAMP. However, it should be noted that a synthetic 5′ppp-ssRNA failed to drive RIG-I signal activation in the absence of at least a short complementary sequence or polynucleotide motifs (see below), suggesting that 5′ppp alone could be insufficient as a determinant of non-self for RIG-I recognition, which may require additional motifs marking an RNA as non-self (Schlee et al., 2009Schlee M. Roth A. Hornung V. Hagmann C.A. Wimmenauer V. Barchet W. Coch C. Janke M. Mihailovic A. Wardle G. et al.Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus.Immunity. 2009; 31: 25-34Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar). A number of studies suggest that sequence composition of an RNA ligand may contribute to the activation of RIG-I-dependent signaling. Two in particular reported that RIG-I preferentially signals IFN expression in response to polyuridine motifs that contain interspersed C nucleotides (known as poly-U/UC; Saito et al., 2008Saito T. Owen D.M. Jiang F. Marcotrigiano J. Gale Jr., M. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.Nature. 2008; 454: 523-527Crossref PubMed Scopus (262) Google Scholar) as present in the genome of hepatitis C virus (HCV) that was produced to include 5′ppp (Saito et al., 2008Saito T. Owen D.M. Jiang F. Marcotrigiano J. Gale Jr., M. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.Nature. 2008; 454: 523-527Crossref PubMed Scopus (262) Google Scholar, Uzri and Gehrke, 2009Uzri D. Gehrke L. Nucleotide sequences and modifications that determine RIG-I/RNA binding and signaling activities.J. Virol. 2009; 83: 4174-4184Crossref PubMed Scopus (52) Google Scholar). Of note is that HCV has a ssRNA genome that is noncapped and includes a 5′ppp. Deletion of the poly-U/UC motif from the HCV genome completely abrogated RIG-I-dependent signaling despite the presence of a 5′ppp within the genome RNA, indicating that 5′ppp is not sufficient to confer RIG-I signaling induction but that additional PAMP motifs are likely to work in concert with 5′ppp to mark an RNA as a RIG-I ligand. In support of this, further analyses revealed that polyuridine-rich RNA motifs serve to enhance RLR signaling to ssRNA PAMPs representing Ebola virus, influenza virus, and other RNA viruses (Saito et al., 2008Saito T. Owen D.M. Jiang F. Marcotrigiano J. Gale Jr., M. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.Nature. 2008; 454: 523-527Crossref PubMed Scopus (262) Google Scholar). In the second study, Gondai et al., 2008Gondai T. Yamaguchi K. Miyano-Kurosaki N. Habu Y. Takaku H. Short-hairpin RNAs synthesized by T7 phage polymerase do not induce interferon.Nucleic Acids Res. 2008; 36: e18Crossref PubMed Scopus (15) Google Scholar showed that extension of in vitro transcribed short hairpin RNAs by one G abolished IFN induction by RIG-I. However, because the addition of the G results in the formation of overhangs that are inhibitory to RIG-I signaling, it is difficult to differentiate whether signaling was abolished because of sequence composition or because of the removal of blunt ends. Overall, these studies serve to indicate that PAMP RNA ligand composition, along with 5′ppp, are important determinants of a non-self signature for RIG-I recognition. Thus, 5′ppp along with the secondary motifs such as polyuridine runs as well as specific
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