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• W3043056027 abstract "•RLRs and several TLRs sense microbial or cellular RNA in several cell compartments•NLRs can directly sense RNA or they regulate other RNA-sensing pathways•DEAD/DEAH-box helicases, hnRNPs, and ZBP1 are emerging RNA sensors or co-sensors•RNA sensor polymorphisms are implicated in autoinflammation and infection Faithful maintenance of immune homeostasis relies on the capacity of the cellular immune surveillance machinery to recognize “nonself”, such as the presence of pathogenic RNA. Several families of pattern-recognition receptors exist that detect immunostimulatory RNA and then induce cytokine-mediated antiviral and proinflammatory responses. Here, we review the distinct features of bona fide RNA sensors, Toll-like receptors and retinoic-acid inducible gene-I (RIG-I)-like receptors in particular, with a focus on their functional specificity imposed by cell-type-dependent expression, subcellular localization, and ligand preference. Furthermore, we highlight recent advances on the roles of nucleotide-binding oligomerization domain (NOD)-like receptors and DEAD-box or DEAH-box RNA helicases in an orchestrated RNA-sensing network and also discuss the relevance of RNA sensor polymorphisms in human disease. Faithful maintenance of immune homeostasis relies on the capacity of the cellular immune surveillance machinery to recognize “nonself”, such as the presence of pathogenic RNA. Several families of pattern-recognition receptors exist that detect immunostimulatory RNA and then induce cytokine-mediated antiviral and proinflammatory responses. Here, we review the distinct features of bona fide RNA sensors, Toll-like receptors and retinoic-acid inducible gene-I (RIG-I)-like receptors in particular, with a focus on their functional specificity imposed by cell-type-dependent expression, subcellular localization, and ligand preference. Furthermore, we highlight recent advances on the roles of nucleotide-binding oligomerization domain (NOD)-like receptors and DEAD-box or DEAH-box RNA helicases in an orchestrated RNA-sensing network and also discuss the relevance of RNA sensor polymorphisms in human disease. Loss of homeostatic control of the immune response is a key determinant of human disease pathogenesis. Exogenous insults such as microbial infection or danger signals from within the cell (e.g., during cell injury) are rapidly recognized by the innate immune system, which elicits host mechanisms to resolve the threats. Failures in tightly regulating these defense mechanisms can lead to detrimental consequences such as chronic infection or autoimmunity. Two major innate immune defense programs are the type I interferon (IFN) and interleukin-1 (IL-1)-mediated proinflammatory responses. While type I IFNs signal through the IFN-α/β receptor (IFNAR) to upregulate IFN-stimulated gene (ISG) products that have antiviral or immunomodulatory activities, IL-1β of the IL-1 cytokine family engages the cognate IL-1 receptor to induce inflammation during microbial infections. Accumulating evidence shows extensive “cross-talk” between type I IFN and IL-1 responses in microbial infections and autoinflammatory disorders, wherein either cooperative or negative regulatory circuits have been reported (Mayer-Barber et al., 2014Mayer-Barber K.D. Andrade B.B. Oland S.D. Amaral E.P. Barber D.L. Gonzales J. Derrick S.C. Shi R. Kumar N.P. Wei W. et al.Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk.Nature. 2014; 511: 99-103Crossref PubMed Scopus (358) Google Scholar, Mayer-Barber and Yan, 2017Mayer-Barber K.D. Yan B. Clash of the cytokine titans: counter-regulation of interleukin-1 and type I interferon-mediated inflammatory responses.Cell. Mol. Immunol. 2017; 14: 22-35Crossref PubMed Scopus (63) Google Scholar). The production of type I IFNs and IL-1β relies on the activation of a set of sensors of the innate immune system, collectively known as pattern-recognition receptors (PRRs). These PRRs survey different cellular compartments and have evolutionarily gained the capability to distinguish foreign or abnormal molecules from host-cell components. Viral RNA species represent a pivotal class of pathogen-associated molecular patterns that activate these sensors. Depending on their cellular localization, which is determined by the route of viral entry and site of virus replication, viral RNA ligands are recognized by one or more specific PRRs that subsequently mount coordinated host responses. Recent advances have expanded the repertoire of immunostimulatory RNA to certain RNA species of host origin, in particular different types of cellular noncoding RNAs. These host RNAs become immunostimulatory when chronically upregulated, mislocalized, and/or misprocessed during viral infection or in disease settings such as autoimmunity. Accordingly, the recognition of cellular immunostimulatory RNAs triggers innate immune responses to combat viral infection, or it can cause chronic inflammation. The vast majority of immunostimulatory RNAs – both pathogen- and host-derived RNAs – reside in the endosome and cytoplasm, where also most RNA sensors are localized. Intriguingly, recent studies show that PRR-mediated RNA sensing can also occur in the nucleus and mitochondrion (Cao et al., 2019aCao L. Liu S. Li Y. Yang G. Luo Y. Li S. Du H. Zhao Y. Wang D. Chen J. et al.The nuclear matrix protein SAFA surveils viral RNA and facilitates immunity by activating antiviral enhancers and super-enhancers.Cell Host Microbe. 2019; 26: 369-384.e368Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Liu et al., 2018Liu G. Lu Y. Thulasi Raman S.N. Xu F. Wu Q. Li Z. Brownlie R. Liu Q. Zhou Y. Nuclear-resident RIG-I senses viral replication inducing antiviral immunity.Nat. Commun. 2018; 9: 3199Crossref PubMed Scopus (14) Google Scholar, Wang et al., 2019Wang Y. Yuan S. Jia X. Ge Y. Ling T. Nie M. Lan X. Chen S. Xu A. Mitochondria-localised ZNFX1 functions as a dsRNA sensor to initiate antiviral responses through MAVS.Nat. Cell Biol. 2019; 21: 1346-1356Crossref Scopus (2) Google Scholar, Zhang et al., 2020Zhang T. Yin C. Boyd D.F. Quarato G. Ingram J.P. Shubina M. Ragan K.B. Ishizuka T. Crawford J.C. Tummers B. et al.Influenza virus Z-RNAs induce ZBP1-mediated necroptosis.Cell. 2020; 180: 1115-1129.e13Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), highlighting an orchestrated multi-compartmental RNA-sensing paradigm. Here, we summarize our current knowledge on classical and emerging RNA sensors and co-sensors of the innate immune system, with an emphasis on their functional distinction imposed by cell-type-dependent expression, subcellular localization, and ligand specificity. We also highlight their physiological roles in type I IFN and IL-1β responses as well as their interdependent regulation. Finally, we discuss the relevance of polymorphisms in genes encoding RNA sensors for human disease conditions. Toll-like receptors (TLRs) represent well-characterized PRRs in mammals whose identification preceded the other PRR families. They are named after the Drosophila Toll proteins, which are involved in Drosophila embryo development and antimicrobial peptide expression (O’Neill et al., 2013O’Neill L.A. Golenbock D. Bowie A.G. The history of Toll-like receptors - redefining innate immunity.Nat. Rev. Immunol. 2013; 13: 453-460Crossref PubMed Scopus (799) Google Scholar). To date, the mammalian TLR family contains 10 (TLR1–TLR10) and 12 (TLR1–TLR9 and TLR11–TLR13) members in human and mouse, respectively, among which TLR3, TLR7, TLR8, and TLR13 sense RNA. TLRs primarily localize to the cell surface and/or endosomes and share a common structural architecture consisting of a leucine-rich repeat (LRR)-containing domain at the amino (N) terminus, a transmembrane domain, and a carboxyl (C)-terminal cytoplasmic Toll/IL-1 receptor (TIR) domain (Jin and Lee, 2008Jin M.S. Lee J.O. Structures of the Toll-like receptor family and its ligand complexes.Immunity. 2008; 29: 182-191Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar). Upon ligand binding to the LRR-containing ectodomain, TLRs predominantly form homodimers that are characterized by an “m”-shaped architecture. Unlike that of most TLRs, the apo form LRR domain of TLR8 has been crystallized as a preexisting inactive homodimer, but not a monomer (Choe et al., 2005Choe J. Kelker M.S. Wilson I.A. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain.Science. 2005; 309: 581-585Crossref PubMed Scopus (445) Google Scholar, Tanji et al., 2013Tanji H. Ohto U. Shibata T. Miyake K. Shimizu T. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands.Science. 2013; 339: 1426-1429Crossref PubMed Scopus (175) Google Scholar, Zhang et al., 2016Zhang Z. Ohto U. Shibata T. Krayukhina E. Taoka M. Yamauchi Y. Tanji H. Isobe T. Uchiyama S. Miyake K. Shimizu T. Structural analysis reveals that Toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA.Immunity. 2016; 45: 737-748Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). In the dimer, the cytoplasmic TIR domains of TLRs are orientated in such a way that allows for the recruitment of downstream adaptor proteins for signal transduction (Figure 1). The myeloid differentiation primary-response protein 88 (MyD88) is the key adaptor of all TLRs except for TLR3. It contains a TIR domain that mediates homotypic interactions with the TIR domain of TLRs. The recruitment of MyD88 triggers the assembly of the “Myddosome”, which is mediated by homotypic interactions between the death domains (DD) of MyD88 and also the DD-DD interactions between MyD88 and IL-1R-associated kinases (IRAKs) such as IRAK1, IRAK2, and IRAK4 (Gay et al., 2011Gay N.J. Gangloff M. O’Neill L.A. What the Myddosome structure tells us about the initiation of innate immunity.Trends Immunol. 2011; 32: 104-109Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). This higher-order complex serves as a signaling platform for the recruitment of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which then activates transforming growth factor β (TGF-β)-activated kinase 1 (TAK1). TAK1 leads to the activation of mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB), and IFN-regulatory factor 5 (IRF5) (Bergstrøm et al., 2015Bergstrøm B. Aune M.H. Awuh J.A. Kojen J.F. Blix K.J. Ryan L. Flo T.H. Mollnes T.E. Espevik T. Stenvik J. TLR8 senses Staphylococcus aureus RNA in human primary monocytes and macrophages and induces IFN-β production via a TAK1-IKKβ-IRF5 signaling pathway.J. Immunol. 2015; 195: 1100-1111Crossref PubMed Scopus (64) Google Scholar, Kawai and Akira, 2010Kawai T. Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.Nat. Immunol. 2010; 11: 373-384Crossref PubMed Scopus (4739) Google Scholar, Takaoka et al., 2005Takaoka A. Yanai H. Kondo S. Duncan G. Negishi H. Mizutani T. Kano S. Honda K. Ohba Y. Mak T.W. Taniguchi T. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.Nature. 2005; 434: 243-249Crossref PubMed Scopus (704) Google Scholar). TLR3 signals exclusively through the TIR-domain-containing adaptor-inducing IFN-β (TRIF) (Hoebe et al., 2003Hoebe K. Du X. Georgel P. Janssen E. Tabeta K. Kim S.O. Goode J. Lin P. Mann N. Mudd S. et al.Identification of Lps2 as a key transducer of MyD88-independent TIR signalling.Nature. 2003; 424: 743-748Crossref PubMed Scopus (960) Google Scholar, Oshiumi et al., 2003Oshiumi H. Matsumoto M. Funami K. Akazawa T. Seya T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction.Nat. Immunol. 2003; 4: 161-167Crossref PubMed Scopus (913) Google Scholar, Yamamoto et al., 2003Yamamoto M. Sato S. Hemmi H. Hoshino K. Kaisho T. Sanjo H. Takeuchi O. Sugiyama M. Okabe M. Takeda K. Akira S. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway.Science. 2003; 301: 640-643Crossref PubMed Scopus (2212) Google Scholar). TRIF interacts with TRAF3 to trigger the TRAF family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1)-IκB kinase ε (IKKε) axis for IRF3 activation, or it associates with TRAF6 and receptor-interacting protein kinase 1 (RIPK1) to activate NF-κB and MAPKs via TAK1 (Kawai and Akira, 2010Kawai T. Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.Nat. Immunol. 2010; 11: 373-384Crossref PubMed Scopus (4739) Google Scholar). In plasmacytoid dendritic cells (pDCs), TLR7 activates IRF7 exclusively through a MyD88-IRAK1/4-TRAF6 axis (Honda et al., 2004Honda K. Yanai H. Mizutani T. Negishi H. Shimada N. Suzuki N. Ohba Y. Takaoka A. Yeh W.C. Taniguchi T. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling.Proc. Natl. Acad. Sci. USA. 2004; 101: 15416-15421Crossref PubMed Scopus (391) Google Scholar, Kawai et al., 2004Kawai T. Sato S. Ishii K.J. Coban C. Hemmi H. Yamamoto M. Terai K. Matsuda M. Inoue J. Uematsu S. et al.Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.Nat. Immunol. 2004; 5: 1061-1068Crossref PubMed Scopus (732) Google Scholar, Uematsu et al., 2005Uematsu S. Sato S. Yamamoto M. Hirotani T. Kato H. Takeshita F. Matsuda M. Coban C. Ishii K.J. Kawai T. et al.Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-alpha induction.J. Exp. Med. 2005; 201: 915-923Crossref PubMed Scopus (0) Google Scholar). The activation of NF-κB, activator protein 1 (AP1), and IRF3 or IRF7 ultimately leads to the expression of type I and III IFNs as well as pro-inflammatory cytokines (Figure 1). The RNA-sensing TLRs are known to recognize their ligands with defined specificity, which has also been supported by structural studies (Table 1). TLR3 contains two RNA-binding sites that recognize double-stranded RNA (dsRNA) in a sequence-independent manner (Alexopoulou et al., 2001Alexopoulou L. Holt A.C. Medzhitov R. Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.Nature. 2001; 413: 732-738Crossref PubMed Scopus (4318) Google Scholar). The minimal dsRNA length required for TLR3 activation in vitro has been shown to be 39–48 bp, which conforms to the length of dsRNA co-crystallized with the TLR3 ectodomains (Leonard et al., 2008Leonard J.N. Ghirlando R. Askins J. Bell J.K. Margulies D.H. Davies D.R. Segal D.M. The TLR3 signaling complex forms by cooperative receptor dimerization.Proc. Natl. Acad. Sci. USA. 2008; 105: 258-263Crossref PubMed Scopus (155) Google Scholar, Liu et al., 2008Liu L. Botos I. Wang Y. Leonard J.N. Shiloach J. Segal D.M. Davies D.R. Structural basis of toll-like receptor 3 signaling with double-stranded RNA.Science. 2008; 320: 379-381Crossref PubMed Scopus (482) Google Scholar). In cells engineered to express intracellular (but not cell-surface-bound) TLR3, a minimal length of 90 bp is required for activation (Leonard et al., 2008Leonard J.N. Ghirlando R. Askins J. Bell J.K. Margulies D.H. Davies D.R. Segal D.M. The TLR3 signaling complex forms by cooperative receptor dimerization.Proc. Natl. Acad. Sci. USA. 2008; 105: 258-263Crossref PubMed Scopus (155) Google Scholar). TLR3 has also been shown to be activated by small interfering RNAs (siRNA) that are ∼20 bp in length (Karikó et al., 2004aKarikó K. Bhuyan P. Capodici J. Weissman D. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3.J. Immunol. 2004; 172: 6545-6549Crossref PubMed Google Scholar, Kleinman et al., 2008Kleinman M.E. Yamada K. Takeda A. Chandrasekaran V. Nozaki M. Baffi J.Z. Albuquerque R.J. Yamasaki S. Itaya M. Pan Y. et al.Sequence- and target-independent angiogenesis suppression by siRNA via TLR3.Nature. 2008; 452: 591-597Crossref PubMed Scopus (724) Google Scholar), though the underlying mechanism of siRNA recognition by TLR3 remains unknown. TLR3 plays an important role in the innate immune response to viral pathogens such as West Nile virus (WNV), influenza A virus (IAV), and poliovirus (Abe et al., 2012Abe Y. Fujii K. Nagata N. Takeuchi O. Akira S. Oshiumi H. Matsumoto M. Seya T. Koike S. The toll-like receptor 3-mediated antiviral response is important for protection against poliovirus infection in poliovirus receptor transgenic mice.J. Virol. 2012; 86: 185-194Crossref PubMed Scopus (0) Google Scholar, Daffis et al., 2008Daffis S. Samuel M.A. Suthar M.S. Gale Jr., M. Diamond M.S. Toll-like receptor 3 has a protective role against West Nile virus infection.J. Virol. 2008; 82: 10349-10358Crossref PubMed Scopus (228) Google Scholar, Le Goffic et al., 2006Le Goffic R. Balloy V. Lagranderie M. Alexopoulou L. Escriou N. Flavell R. Chignard M. Si-Tahar M. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia.PLoS Pathog. 2006; 2: e53Crossref PubMed Scopus (361) Google Scholar, Wang et al., 2004Wang T. Town T. Alexopoulou L. Anderson J.F. Fikrig E. Flavell R.A. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis.Nat. Med. 2004; 10: 1366-1373Crossref PubMed Scopus (797) Google Scholar); however, the physiological TLR3 ligands in these contexts remain uncharacterized, except for poliovirus-derived RNA harboring stem-loop core structures (Tatematsu et al., 2013Tatematsu M. Nishikawa F. Seya T. Matsumoto M. Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA.Nat. Commun. 2013; 4: 1833Crossref PubMed Scopus (53) Google Scholar). In myeloid DCs, TLR3 also responds to phagocytosed RNA of viral (and likely also host) origin (Karikó et al., 2004bKarikó K. Ni H. Capodici J. Lamphier M. Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3.J. Biol. Chem. 2004; 279: 12542-12550Crossref PubMed Scopus (702) Google Scholar, Tatematsu et al., 2013Tatematsu M. Nishikawa F. Seya T. Matsumoto M. Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA.Nat. Commun. 2013; 4: 1833Crossref PubMed Scopus (53) Google Scholar), and phagocytosed viral RNA enhances cross-priming of cytotoxic T cells (Schulz et al., 2005Schulz O. Diebold S.S. Chen M. Näslund T.I. Nolte M.A. Alexopoulou L. Azuma Y.T. Flavell R.A. Liljeström P. Reis e Sousa C. Toll-like receptor 3 promotes cross-priming to virus-infected cells.Nature. 2005; 433: 887-892Crossref PubMed Scopus (623) Google Scholar). TLR7 and TLR8 are highly homologous RNA sensors with an RNA ligand preference for single-stranded RNA (ssRNA) (Diebold et al., 2004Diebold S.S. Kaisho T. Hemmi H. Akira S. Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.Science. 2004; 303: 1529-1531Crossref PubMed Scopus (2220) Google Scholar, Heil et al., 2004Heil F. Hemmi H. Hochrein H. Ampenberger F. Kirschning C. Akira S. Lipford G. Wagner H. Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.Science. 2004; 303: 1526-1529Crossref PubMed Scopus (2611) Google Scholar, Lund et al., 2004Lund J.M. Alexopoulou L. Sato A. Karow M. Adams N.C. Gale N.W. Iwasaki A. Flavell R.A. Recognition of single-stranded RNA viruses by Toll-like receptor 7.Proc. Natl. Acad. Sci. USA. 2004; 101: 5598-5603Crossref PubMed Scopus (1301) Google Scholar). In humans, TLR7 is primarily expressed in pDCs and B cells, while TLR8 is expressed in myeloid DCs, monocytes, and monocyte-derived DCs (Gorden et al., 2005Gorden K.B. Gorski K.S. Gibson S.J. Kedl R.M. Kieper W.C. Qiu X. Tomai M.A. Alkan S.S. Vasilakos J.P. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8.J. Immunol. 2005; 174: 1259-1268Crossref PubMed Google Scholar). Both TLRs contain two RNA ligand-binding sites within their LRR domain, designated site 1 and site 2, both of which are indispensable for TLR7 and TLR8 activation. The site 1 is a highly conserved binding site for nucleosides, with TLR7 and TLR8 having a preference for guanosine (G) and uridine (U), respectively (Tanji et al., 2015Tanji H. Ohto U. Shibata T. Taoka M. Yamauchi Y. Isobe T. Miyake K. Shimizu T. Toll-like receptor 8 senses degradation products of single-stranded RNA.Nat. Struct. Mol. Biol. 2015; 22: 109-115Crossref PubMed Scopus (121) Google Scholar, Zhang et al., 2016Zhang Z. Ohto U. Shibata T. Krayukhina E. Taoka M. Yamauchi Y. Tanji H. Isobe T. Uchiyama S. Miyake K. Shimizu T. Structural analysis reveals that Toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA.Immunity. 2016; 45: 737-748Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, Zhang et al., 2018bZhang Z. Ohto U. Shibata T. Taoka M. Yamauchi Y. Sato R. Shukla N.M. David S.A. Isobe T. Miyake K. Shimizu T. Structural analyses of Toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands.Cell Rep. 2018; 25: 3371-3381.e3375Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). The oligonucleotide-binding activity is conferred by site 2. While TLR8 binds the UG dinucleotide, TLR7 requires at least a 3-mer motif containing a U in the second position. Further analysis reveals that the site 2 ssRNA sequence preference is UU(U/C) > UU(G/A) > XUX (where X stands for non-U) (Tanji et al., 2015Tanji H. Ohto U. Shibata T. Taoka M. Yamauchi Y. Isobe T. Miyake K. Shimizu T. Toll-like receptor 8 senses degradation products of single-stranded RNA.Nat. Struct. Mol. Biol. 2015; 22: 109-115Crossref PubMed Scopus (121) Google Scholar, Zhang et al., 2016Zhang Z. Ohto U. Shibata T. Krayukhina E. Taoka M. Yamauchi Y. Tanji H. Isobe T. Uchiyama S. Miyake K. Shimizu T. Structural analysis reveals that Toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA.Immunity. 2016; 45: 737-748Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, Zhang et al., 2018bZhang Z. Ohto U. Shibata T. Taoka M. Yamauchi Y. Sato R. Shukla N.M. David S.A. Isobe T. Miyake K. Shimizu T. Structural analyses of Toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands.Cell Rep. 2018; 25: 3371-3381.e3375Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). However, it remains unclear how exactly physiological ssRNAs activate TLR7 and TLR8 by coordinating both binding sites. To date, TLR7 has been shown to mediate type I IFN responses to several RNA viruses, such as IAV, vesicular stomatitis virus (VSV), and human immunodeficiency virus-1 (HIV-1) (Diebold et al., 2004Diebold S.S. Kaisho T. Hemmi H. Akira S. Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.Science. 2004; 303: 1529-1531Crossref PubMed Scopus (2220) Google Scholar, Heil et al., 2004Heil F. Hemmi H. Hochrein H. Ampenberger F. Kirschning C. Akira S. Lipford G. Wagner H. Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.Science. 2004; 303: 1526-1529Crossref PubMed Scopus (2611) Google Scholar, Lee et al., 2007Lee H.K. Lund J.M. Ramanathan B. Mizushima N. Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells.Science. 2007; 315: 1398-1401Crossref PubMed Scopus (623) Google Scholar, Lund et al., 2004Lund J.M. Alexopoulou L. Sato A. Karow M. Adams N.C. Gale N.W. Iwasaki A. Flavell R.A. Recognition of single-stranded RNA viruses by Toll-like receptor 7.Proc. Natl. Acad. Sci. USA. 2004; 101: 5598-5603Crossref PubMed Scopus (1301) Google Scholar). The detailed ligand characteristics of a few microbial and cellular TLR7 agonists have been identified, which include HIV-derived GU-rich ssRNA, microRNA let-7, and multiple siRNA sequences (Heil et al., 2004Heil F. Hemmi H. Hochrein H. Ampenberger F. Kirschning C. Akira S. Lipford G. Wagner H. Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.Science. 2004; 303: 1526-1529Crossref PubMed Scopus (2611) Google Scholar, Hornung et al., 2005Hornung V. Guenthner-Biller M. Bourquin C. Ablasser A. Schlee M. Uematsu S. Noronha A. Manoharan M. Akira S. de Fougerolles A. et al.Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7.Nat. Med. 2005; 11: 263-270Crossref PubMed Scopus (950) Google Scholar, Lehmann et al., 2012Lehmann S.M. Krüger C. Park B. Derkow K. Rosenberger K. Baumgart J. Trimbuch T. Eom G. Hinz M. Kaul D. et al.An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration.Nat. Neurosci. 2012; 15: 827-835Crossref PubMed Scopus (384) Google Scholar). The orphan receptor TLR13 is a mouse-specific endosomal TLR that is predominantly expressed in DCs and macrophages. It recognizes bacterially and virally derived RNAs, leading to proinflammatory and type I IFN responses through NF-κB and IRF7, respectively (Hidmark et al., 2012Hidmark A. von Saint Paul A. Dalpke A.H. Cutting edge: TLR13 is a receptor for bacterial RNA.J. Immunol. 2012; 189: 2717-2721Crossref PubMed Scopus (73) Google Scholar, Shi et al., 2011Shi Z. Cai Z. Sanchez A. Zhang T. Wen S. Wang J. Yang J. Fu S. Zhang D. A novel Toll-like receptor that recognizes vesicular stomatitis virus.J. Biol. Chem. 2011; 286: 4517-4524Crossref PubMed Scopus (114) Google Scholar). Furthermore, the bacterial 23S ribosomal RNA (rRNA) has been identified to be a physiological ligand of TLR13. This RNA contains a highly conserved 13-nt sequence within the ribozyme catalytic domain that mediates TLR13 activation in vitro and in vivo (Li and Chen, 2012Li X.D. Chen Z.J. Sequence specific detection of bacterial 23S ribosomal RNA by TLR13.eLife. 2012; 1: e00102Crossref PubMed Scopus (77) Google Scholar, Oldenburg et al., 2012Oldenburg M. Krüger A. Ferstl R. Kaufmann A. Nees G. Sigmund A. Bathke B. Lauterbach H. Suter M. Dreher S. et al.TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification.Science. 2012; 337: 1111-1115Crossref PubMed Scopus (252) Google Scholar). Structural analysis of the TLR13 ectodomain in complex with the 23S rRNA-derived 13-nt ssRNA reveals that a unique RNA stem-loop structure is crucial for TLR13 binding in a sequence- and conformation-specific manner. A similar RNA motif activating TLR13 is found in the VSV genome (Shi et al., 2011Shi Z. Cai Z. Sanchez A. Zhang T. Wen S. Wang J. Yang J. Fu S. Zhang D. A novel Toll-like receptor that recognizes vesicular stomatitis virus.J. Biol. Chem. 2011; 286: 4517-4524Crossref PubMed Scopus (114) Google Scholar, Song et al., 2015Song W. Wang J. Han Z. Zhang Y. Zhang H. Wang W. Chang J. Xia B. Fan S. Zhang D. et al.Structural basis for specific recognition of single-stranded RNA by Toll-like receptor 13.Nat. Struct. Mol. Biol. 2015; 22: 782-787Crossref PubMed Scopus (28) Google Scholar) (Table 1).Table 1TLR and RLR LigandsSensorsLigand CharacteristicsSynthetic RNAMicrobial RNAHost RNAKey ReferencesTLR3dsRNAdsRNA ≥39–48 bpViral and bacterial RNA (e.g., long stem-loop containing poliovirus-derived RNA)Phagocytosed host RNA (context dependent)Karikó et al., 2004aKarikó K. Bhuyan P. Capodici J. Weissman D. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3.J. Immunol. 2004; 172: 6545-6549Crossref PubMed Google Scholar, Karikó et al., 2004bKarikó K. Ni H. Capodici J. Lamphier M. Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3.J. Biol. Chem. 2004; 279: 12542-12550Crossref PubMed Scopus (702) Google Scholar, Kleinman et al., 2008Kleinman M.E. Yamada K. Takeda A. Chandrasekaran V. Nozaki M. Baffi J.Z. Albuquerque R.J. Yamasaki S. Itaya M. Pan Y. et al.Sequence- and target-independent angiogenesis suppression by siRNA via TLR3.Nature. 2008; 452: 591-597Crossref PubMed Scopus (724) Google Scholar, Leonard et al., 2008Leonard J.N. Ghirlando R. Askins J. Bell J.K. Margulies D.H. Davies D.R. Segal D.M. The TLR3 signaling complex forms by cooperative receptor dimerization.Proc. Natl. Acad. Sci. USA. 2008; 105: 258-263Crossref PubMed Scopus (155) Google Scholar, Liu et al., 2008Liu L. Botos I. Wang Y. Leonard J.N. Shiloach J. Segal D.M. Davies D.R. Structural basis of toll-like receptor 3 signaling with double-stranded RNA.Science. 2008; 320: 379-381Crossref PubMed Scopus (482) Google Scholar, Tatematsu et al., 2013Tatematsu M. Nishikawa F. Seya T. Matsumoto M. 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• W3043056027 created "2020-07-23" @default.
• W3043056027 creator A5016975145 @default.
• W3043056027 creator A5070822882 @default.
• W3043056027 date "2020-07-01" @default.
• W3043056027 modified "2023-10-13" @default.
• W3043056027 title "Distinct and Orchestrated Functions of RNA Sensors in Innate Immunity" @default.
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