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• W3042281681 abstract "All lifeforms have developed highly sophisticated systems equipped to detect altered self and non-self nucleic acids (NA). In vertebrates, NA-sensing receptors safeguard the integrity of the organism by detecting pathogens, dyshomeostasis and damage, and inducing appropriate responses to eliminate pathogens and reconstitute homeostasis. Effector mechanisms include i) immune signaling, ii) restriction of NA functions such as inhibition of mRNA translation, and iii) cell death pathways. An appropriate effector response is necessary for host defense, but dysregulated NA-sensing can lead to devastating autoimmune and autoinflammatory disease. Their inherent biochemical similarity renders the reliable distinction between self NA under homeostatic conditions and altered or exogenous NA particularly challenging. In this review, we provide an overview of recent progress in our understanding of the closely coordinated and regulated network of innate immune receptors, restriction factors, and nucleases to effectively respond to pathogens and maintain host integrity. All lifeforms have developed highly sophisticated systems equipped to detect altered self and non-self nucleic acids (NA). In vertebrates, NA-sensing receptors safeguard the integrity of the organism by detecting pathogens, dyshomeostasis and damage, and inducing appropriate responses to eliminate pathogens and reconstitute homeostasis. Effector mechanisms include i) immune signaling, ii) restriction of NA functions such as inhibition of mRNA translation, and iii) cell death pathways. An appropriate effector response is necessary for host defense, but dysregulated NA-sensing can lead to devastating autoimmune and autoinflammatory disease. Their inherent biochemical similarity renders the reliable distinction between self NA under homeostatic conditions and altered or exogenous NA particularly challenging. In this review, we provide an overview of recent progress in our understanding of the closely coordinated and regulated network of innate immune receptors, restriction factors, and nucleases to effectively respond to pathogens and maintain host integrity. Nucleic acids (NA) are a common building block of life, yet detection of exogenous genetic material is essential to host defense. The immune sensors employed by our cells to distinguish between self and non-self NA are both effective and ancient, with recent publications revealing that even bacteria utilize sensors surprisingly similar to our own, such as cGAMP synthase (cGAS) and Toll-interleukin Receptor (TIR) domain-containing proteins for anti-phage defense (Cohen et al., 2019Cohen D. Melamed S. Millman A. Shulman G. Oppenheimer-Shaanan Y. Kacen A. Doron S. Amitai G. Sorek R. Cyclic GMP-AMP signalling protects bacteria against viral infection.Nature. 2019; 574: 691-695Crossref PubMed Scopus (23) Google Scholar; Doron et al., 2018Doron S. Melamed S. Ofir G. Leavitt A. Lopatina A. Keren M. Amitai G. Sorek R. Systematic discovery of antiphage defense systems in the microbial pangenome.Science. 2018; 359: eaar4120Crossref PubMed Scopus (143) Google Scholar). Although there are also sequence-based, adaptive forms of NA sensing such as CRISPR/Cas and RNA interference (RNAi), which are integral to host defense in other kingdoms and phyla (Berkhout, 2018Berkhout B. RNAi-mediated antiviral immunity in mammals.Curr. Opin. Virol. 2018; 32: 9-14Crossref PubMed Scopus (9) Google Scholar; Hampton et al., 2020Hampton H.G. Watson B.N.J. Fineran P.C. The arms race between bacteria and their phage foes.Nature. 2020; 577: 327-336Crossref PubMed Scopus (7) Google Scholar), chordates principally rely on a discreet but powerful system of germline-encoded NA sensors that are activated by molecular hallmarks of non-self or altered self NA (Schlee and Hartmann, 2016Schlee M. Hartmann G. Discriminating self from non-self in nucleic acid sensing.Nat. Rev. Immunol. 2016; 16: 566-580Crossref PubMed Scopus (180) Google Scholar). Sensor activation triggers a transcriptional form of host defense, including type-I interferon (IFN-I) release and the autocrine and paracrine induction of interferon-stimulated genes (ISG), known as the antiviral state. In turn, to avoid immunodetection, pathogens and viruses in particular have engaged in a type of “nucleic acid arms race” to avoid sensing by the host. Pathogens can sequester their NA (e.g., in replication organelles), mask them with characteristics of self (e.g., viral cap-snatching), or even directly disable host signaling. Indeed, recent publications indicate that, while RNAi is present in vertebrate cells and active in embryonic cells (Li et al., 2013aLi Y. Lu J. Han Y. Fan X. Ding S.-W. RNA interference functions as an antiviral immunity mechanism in mammals.Science. 2013; 342: 231-234Crossref PubMed Scopus (207) Google Scholar; Maillard et al., 2013Maillard P.V. Ciaudo C. Marchais A. Li Y. Jay F. Ding S.W. Voinnet O. Antiviral RNA interference in mammalian cells.Science. 2013; 342: 235-238Crossref PubMed Scopus (226) Google Scholar), it can be rendered ineffective by the anti-RNAi mechanisms of many viruses (Li et al., 2016Li Y. Basavappa M. Lu J. Dong S. Cronkite D.A. Prior J.T. Reinecker H.-C. Hertzog P. Han Y. Li W.-X. et al.Induction and suppression of antiviral RNA interference by influenza A virus in mammalian cells.Nat. Microbiol. 2016; 2: 16250-16259Crossref PubMed Scopus (57) Google Scholar; Qiu et al., 2017Qiu Y. Xu Y. Zhang Y. Zhou H. Deng Y.-Q. Li X.-F. Miao M. Zhang Q. Zhong B. Hu Y. et al.Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals.Immunity. 2017; 46: 992-1004.e5Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Thus, it is tempting to speculate that this disabling of RNAi provided the evolutionary pressure leading to the dominance of the type-I interferon (IFN-I) signaling in vertebrate antiviral defense, a system which is both exceptionally potent and reciprocally antagonistic with RNAi (Maillard et al., 2016Maillard P.V. Van der Veen A.G. Deddouche-Grass S. Rogers N.C. Merits A. Reis e Sousa C. Inactivation of the type I interferon pathway reveals long double-stranded RNA-mediated RNA interference in mammalian cells.EMBO J. 2016; 35: 2505-2518Crossref PubMed Scopus (44) Google Scholar; Seo et al., 2013Seo G.J. Kincaid R.P. Phanaksri T. Burke J.M. Pare J.M. Cox J.E. Hsiang T.-Y. Krug R.M. Sullivan C.S. Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells.Cell Host Microbe. 2013; 14: 435-445Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). It is interesting to note that, although many of the receptors activating type-I IFN signaling are highly conserved evolutionarily, their downstream signaling is unique to chordates. Analogously, caspases and metacaspases are ancient participants in programmed cell death (Bell and Megeney, 2017Bell R.A.V. Megeney L.A. Evolution of caspase-mediated cell death and differentiation: twins separated at birth.Cell Death Differ. 2017; 24: 1359-1368Crossref PubMed Scopus (42) Google Scholar), yet inflammatory caspase activation by inflammasome proteins, some of which can also be activated directly or indirectly by NA, is unique to vertebrates (Maltez and Miao, 2016Maltez V.I. Miao E.A. Reassessing the Evolutionary Importance of Inflammasomes.J. Immunol. 2016; 196: 956-962Crossref PubMed Scopus (22) Google Scholar). In particular, DNA sensing by inflammasomes is subject to strong evolutionary pressure and divergence even among mammalian species (Brunette et al., 2012Brunette R.L. Young J.M. Whitley D.G. Brodsky I.E. Malik H.S. Stetson D.B. Extensive evolutionary and functional diversity among mammalian AIM2-like receptors.J. Exp. Med. 2012; 209: 1969-1983Crossref PubMed Scopus (120) Google Scholar; Gaidt et al., 2017Gaidt M.M. Ebert T.S. Chauhan D. Ramshorn K. Pinci F. Zuber S. O’Duill F. Schmid-Burgk J.L. Hoss F. Buhmann R. et al.The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3.Cell. 2017; 171: 1110-1124.e18Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Indeed, the functionalization of CRISPR/Cas systems as a tool for genomic editing have revealed important differences in human and murine NA sensing, including distinct cell subset expression patterns of NA-sensing Toll-Like Receptors (TLRs) or species differences in the structural requirements for the detection of cyclic dinucleotide cGAMP by STING. In this review, we will focus on the specific molecular mechanisms employed by the nucleic acid sensors of the vertebrate innate immune system to distinguish between physiologically present and pathogen-derived or pathogenically altered NA. We primarily focus on the distinction of self versus non self, and the molecular structure, availability, and localization of NA ligands. Our aim is to provide sufficient background to understand these findings within the broader context of the evolving field of nucleic acid immunity. Special emphasis is placed on what we think is essential information for someone who is new to the field, such as the spectrum of antiviral responses elicited (see Box 1, effector functions), the multiple issues around the first NA ligand “poly(I:C)” (see Box 2, polyI:C), or the advantages and disadvantages of using the most common enzymatic method for RNA synthesis, in vitro transcription (IVT), and its implications for RIG-I activation (see Box 3, in-vitro transcription).Box 1Effector Functions of Nucleic Acid Sensing: Signaling, Restriction, and Cell DeathUpon NA binding, immune sensing receptors activate an overwhelmingly transcriptional response. These signaling transduction cascades include nuclear factor-κB (NF-κB), interferon regulatory factors(IRF) 3 and 7 and activator protein-1 (AP-1) (Maniatis et al., 1998Maniatis T. Falvo J.V. Kim T.H. Kim T.K. Lin C.H. Parekh B.S. Wathelet M.G. Structure and function of the interferon-beta enhanceosome.Cold Spring Harb. Symp. Quant. Biol. 1998; 63: 609-620Crossref PubMed Google Scholar; Marié et al., 1998Marié I. Durbin J.E. Levy D.E. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7.EMBO J. 1998; 17: 6660-6669Crossref PubMed Google Scholar), which cooperatively transcribe chemokines and cytokines as well as type-I and, at mucosal barriers, type-III interferons (Onoguchi et al., 2007Onoguchi K. Yoneyama M. Takemura A. Akira S. Taniguchi T. Namiki H. Fujita T. Viral infections activate types I and III interferon genes through a common mechanism.J. Biol. Chem. 2007; 282: 7576-7581Crossref PubMed Scopus (257) Google Scholar; Ye et al., 2019Ye L. Schnepf D. Staeheli P. Interferon-λ orchestrates innate and adaptive mucosal immune responses.Nat. Rev. Immunol. 2019; 19: 614-625Crossref PubMed Scopus (20) Google Scholar). This results in a complexly orchestrated response, including the induction of interferon-stimulated genes (ISG) and the anti-viral state in infected and bystander cells, as well as the activation and the recruitment of innate and adaptive immune cells to the site of infection (González-Navajas et al., 2012González-Navajas J.M. Lee J. David M. Raz E. Immunomodulatory functions of type I interferons.Nat. Rev. Immunol. 2012; 12 (Published online January 6, 2012): 125-135Crossref PubMed Scopus (554) Google Scholar).In contrast, NA restriction factors do not induce transcriptional signaling but rather serve to directly restrict the function of pathogen nucleic acids via their sequestration, destruction, and processing and/or presentation for NA immune sensing receptors. These factors are generally ISGs, and their presence is indicative of the anti-viral state. Restriction mechanisms can be highly specific, such as the sequestration of 2′O-unmethylated capped RNA by IFIT1 (Daffis et al., 2010Daffis S. Szretter K.J. Schriewer J. Li J. Youn S. Errett J. Lin T.-Y. Schneller S. Züst R. Dong H. et al.2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members.Nature. 2010; 468: 452-456Crossref PubMed Scopus (396) Google Scholar) or global, such as protein kinase R activation, which upon binding of long double-stranded(ds)RNA induces the inhibition of cellular transcription and translation, halting the proliferation of cell and virus alike (Levin and London, 1978Levin D. London I.M. Regulation of protein synthesis: activation by double-stranded RNA of a protein kinase that phosphorylates eukaryotic initiation factor 2.Proc. Natl. Acad. Sci. USA. 1978; 75: 1121-1125Crossref PubMed Google Scholar).The ultima ratio of global pathogen restriction in host defense is cell death, which simultaneously restricts pathogen replication, releases inflammatory mediators, and terminates transcriptional signaling (Maelfait et al., 2020Maelfait J. Liverpool L. Rehwinkel J. Nucleic Acid Sensors and Programmed Cell Death.J. Mol. Biol. 2020; 432: 552-568Crossref PubMed Scopus (4) Google Scholar). NA-sensing can trigger a variety of forms of programmed cell death (PCD) from immunologically silent to proinflammatory. Apoptosis can result from overwhelming activation of NA sensors, such as STING (Gulen et al., 2017Gulen M.F. Koch U. Haag S.M. Schuler F. Apetoh L. Villunger A. Radtke F. Ablasser A. Signalling strength determines proapoptotic functions of STING.Nat. Commun. 2017; 8: 427Crossref PubMed Scopus (76) Google Scholar; Tang et al., 2016Tang C.-H.A. Zundell J.A. Ranatunga S. Lin C. Nefedova Y. Del Valle J.R. Hu C.-C.A. Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells.Cancer Res. 2016; 76: 2137-2152Crossref PubMed Scopus (77) Google Scholar) or MAVS (Besch et al., 2009Besch R. Poeck H. Hohenauer T. Senft D. Häcker G. Berking C. Hornung V. Endres S. Ruzicka T. Rothenfusser S. Hartmann G. Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells.J. Clin. Invest. 2009; 119: 2399-2411Crossref PubMed Google Scholar; Kaneda, 2013Kaneda Y. The RIG-I/MAVS signaling pathway in cancer cell-selective apoptosis.OncoImmunology. 2013; 2: e23566Crossref PubMed Scopus (11) Google Scholar; Matsushima-Miyagi et al., 2012Matsushima-Miyagi T. Hatano K. Nomura M. Li-Wen L. Nishikawa T. Saga K. Shimbo T. Kaneda Y. TRAIL and Noxa are selectively upregulated in prostate cancer cells downstream of the RIG-I/MAVS signaling pathway by nonreplicating Sendai virus particles.Clin. Cancer Res. 2012; 18: 6271-6283Crossref PubMed Scopus (58) Google Scholar), particularly in cancer cells. Necroptosis, a lytic proinflammatory form of PCD, can be directly induced by the activation of the ZBP-1 by viral or endogenous Z-form RNA(Maelfait et al., 2017Maelfait J. Liverpool L. Bridgeman A. Ragan K.B. Upton J.W. Rehwinkel J. Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis.EMBO J. 2017; 36: 2529-2543Crossref PubMed Scopus (35) Google Scholar; Thapa et al., 2016Thapa R.J. Ingram J.P. Ragan K.B. Nogusa S. Boyd D.F. Benitez A.A. Sridharan H. Kosoff R. Shubina M. Landsteiner V.J. et al.DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death.Cell Host Microbe. 2016; 20: 674-681Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar) but also indirectly by combined TNF and IFN exposure downstream of STING or MAVS hyperactivation (Brault et al., 2018Brault M. Olsen T.M. Martinez J. Stetson D.B. Oberst A. Intracellular Nucleic Acid Sensing Triggers Necroptosis through Synergistic Type I IFN and TNF Signaling.J. Immunol. 2018; 200: 2748-2756Crossref PubMed Scopus (12) Google Scholar). Pyroptosis, a rapid, lytic form of PCD accompanied by the release of pyrogenic cytokines, results from inflammasome activation and can be triggered directly by NA-sensing inflammasome proteins or indirectly downstream of NA sensing. In particular, the NLRP3 inflammasome is activated by cellular dyshomeostasis and thus induces pyroptosis secondary to other cell death pathways(de Vasconcelos and Lamkanfi, 2020de Vasconcelos N.M. Lamkanfi M. Recent Insights on Inflammasomes, Gasdermin Pores, and Pyroptosis.Cold Spring Harb. Perspect. Biol. 2020; 12: a036392Crossref PubMed Scopus (3) Google Scholar), as has been described downstream of STING, MAVS, and ZBP-1 activation, as well as viral lytic cell death (da Costa et al., 2019da Costa L.S. Outlioua A. Anginot A. Akarid K. Arnoult D. RNA viruses promote activation of the NLRP3 inflammasome through cytopathogenic effect-induced potassium efflux.Cell Death Dis. 2019; 10 (Published online April 25, 2019)https://doi.org/10.1038/s41419-019-1579-0Crossref PubMed Scopus (11) Google Scholar; Franchi et al., 2014Franchi L. Eigenbrod T. Muñoz-Planillo R. Ozkurede U. Kim Y.G. Arindam C. Gale Jr., M. Silverman R.H. Colonna M. Akira S. Núñez G. Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux.J. Immunol. 2014; 193: 4214-4222Crossref PubMed Scopus (66) Google Scholar; Gaidt et al., 2017Gaidt M.M. Ebert T.S. Chauhan D. Ramshorn K. Pinci F. Zuber S. O’Duill F. Schmid-Burgk J.L. Hoss F. Buhmann R. et al.The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3.Cell. 2017; 171: 1110-1124.e18Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar; Kuriakose et al., 2016Kuriakose T. Man S.M. Malireddi R.K.S. Karki R. Kesavardhana S. Place D.E. Neale G. Vogel P. Kanneganti T.-D. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways.Sci. Immunol. 2016; 1: aag2045Crossref PubMed Google Scholar). Since canonical inflammasome assembly induces caspase-1-mediated proteolytic activation of both the pyroptotic effector gasdermin D as well as cytokines from the IL-1 family, it sits at the crossroads of signaling and effector functions (de Vasconcelos and Lamkanfi, 2020de Vasconcelos N.M. Lamkanfi M. Recent Insights on Inflammasomes, Gasdermin Pores, and Pyroptosis.Cold Spring Harb. Perspect. Biol. 2020; 12: a036392Crossref PubMed Scopus (3) Google Scholar). However, it should be noted that this type of signaling is fundamentally different from the IFN and ISG response: inflammasome activation is post-translational, not transcriptional and, theoretically, does not even requiring a living cell (Franklin et al., 2018Franklin B.S. Latz E. Schmidt F.I. The intra- and extracellular functions of ASC specks.Immunol. Rev. 2018; 281: 74-87Crossref PubMed Scopus (19) Google Scholar). Nonetheless, inflammasome activation is of critical importance to the immune response to many viral infections, since IL-1 family cytokines support immune cell recruitment, NK-cell activation and the formation of anti-viral CD8+ T cell responses (reviewed in Kanneganti, 2010Kanneganti T.-D. Central roles of NLRs and inflammasomes in viral infection.Nat. Rev. Immunol. 2010; 10: 688-698Crossref PubMed Scopus (269) Google Scholar).Since the type-I IFN response is inherently transcriptional, NA-induced cell death also acts as an important limiter of antiviral responses. Several studies have demonstrated that apoptotic caspases directly inhibit cGAS/STING signaling (Rongvaux et al., 2014Rongvaux A. Jackson R. Harman C.C.D. Li T. West A.P. de Zoete M.R. Wu Y. Yordy B. Lakhani S.A. Kuan C.-Y. et al.Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA.Cell. 2014; 159: 1563-1577Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar; White et al., 2014White M.J. McArthur K. Metcalf D. Lane R.M. Cambier J.C. Herold M.J. van Delft M.F. Bedoui S. Lessene G. Ritchie M.E. et al.Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.Cell. 2014; 159: 1549-1562Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar), with a recent report showing that activated caspase 3 can cleave cGAS, MAVS, and IRF3(Ning et al., 2019Ning X. Wang Y. Jing M. Sha M. Lv M. Gao P. Zhang R. Huang X. Feng J.-M. Jiang Z. Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3.Mol. Cell. 2019; 74: 19-31.e7Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). Similar mechanisms have been demonstrated for pyroptosis. Activated caspase 1 has been reported to cleave cGAS (Wang et al., 2017Wang Y. Ning X. Gao P. Wu S. Sha M. Lv M. Zhou X. Gao J. Fang R. Meng G. et al.Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection.Immunity. 2017; 46: 393-404Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), and activation of gasdermin D-mediated pyroptosis can also resolve cGAS/STING signaling through K+ efflux (Banerjee et al., 2018Banerjee I. Behl B. Mendonca M. Shrivastava G. Russo A.J. Menoret A. Ghosh A. Vella A.T. Vanaja S.K. Sarkar S.N. et al.Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis.Immunity. 2018; 49: 413-426.e5Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Although many recent studies to date have focused on the effect of PCD on cGAS/STING, the reciprocal interplay between NA sensing and cell death is undoubtedly important for all NA-sensing pathways and continues to be the focus of intense research.Box 2Poly I:CGenerated by the annealing of enzymatically generated inosine and cytosine homopolymers (Michelson et al., 1967Michelson A.M. Massoulié J. Guschlbauer W. Synthetic polynucleotides.Prog. Nucleic Acid Res. Mol. Biol. 1967; 6: 83-141Crossref PubMed Google Scholar), polyI:C is by far the most commonly used RNA ligand in research. Clinical applications for polyI:C were explored soon after the discovery that it could produce a robust IFN response (Field et al., 1967Field A.K. Tytell A.A. Lampson G.P. Hilleman M.R. Inducers of interferon and host resistance. II. Multistranded synthetic polynucleotide complexes.Proc. Natl. Acad. Sci. USA. 1967; 58: 1004-1010Crossref PubMed Scopus (534) Google Scholar; Hilleman, 1970Hilleman M.R. Prospects for the use of double-stranded ribonucleic acid (poly I:C) inducers in man.J. Infect. Dis. 1970; 121: 196-211Crossref PubMed Google Scholar), and clinical trials using polyI:C in tumor immunotherapy continue today (e.g., NCT02166905, NCT03358719). Moreover, over the last 50 years, intense research has focused on characterizing the immune sensor(s) polyI:C activates. This popularity is remarkable given that polyI:C is neither a physiological ligand nor is its mode of action well defined. Rather, its widespread use results from its amenability to enzymatic synthesis (Michelson et al., 1967Michelson A.M. Massoulié J. Guschlbauer W. Synthetic polynucleotides.Prog. Nucleic Acid Res. Mol. Biol. 1967; 6: 83-141Crossref PubMed Google Scholar) and its unique ability to induce a robust type-I IFN response compared to other annealed homopolymers (Field et al., 1967Field A.K. Tytell A.A. Lampson G.P. Hilleman M.R. Inducers of interferon and host resistance. II. Multistranded synthetic polynucleotide complexes.Proc. Natl. Acad. Sci. USA. 1967; 58: 1004-1010Crossref PubMed Scopus (534) Google Scholar), a feature which remains poorly understood. As a long dsRNA with a 5′ diphosphate terminus, polyI:C is known to activate the sensing receptors TLR3, MDA5, and RIG-I (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; Gitlin et al., 2006Gitlin L. Barchet W. Gilfillan S. Cella M. Beutler B. Flavell R.A. Diamond M.S. Colonna M. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus.Proc. Natl. Acad. Sci. USA. 2006; 103: 8459-8464Crossref PubMed Scopus (807) Google Scholar; 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 (943) Google Scholar; 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 (2311) Google Scholar; Kato 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 (987) 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: 2851-2858Crossref PubMed Google Scholar), accessory proteins such including LGP2 and members of the DDX and DHX families (reviewed in Oshiumi et al., 2016Oshiumi H. Kouwaki T. Seya T. Accessory Factors of Cytoplasmic Viral RNA Sensors Required for Antiviral Innate Immune Response.Front. Immunol. 2016; 7: 200Crossref PubMed Scopus (28) Google Scholar) as well as the restriction factors PKR and the OAS family (Farrell et al., 1978Farrell P.J. Sen G.C. Dubois M.F. Ratner L. Slattery E. Lengyel P. Interferon action: two distinct pathways for inhibition of protein synthesis by double-stranded RNA.Proc. Natl. Acad. Sci. USA. 1978; 75: 5893-5897Crossref PubMed Google Scholar; Hovanessian et al., 1977Hovanessian A.G. Brown R.E. Kerr I.M. Synthesis of low molecular weight inhibitor of protein synthesis with enzyme from interferon-treated cells.Nature. 1977; 268: 537-540Crossref PubMed Google Scholar; Zilberstein et al., 1978Zilberstein A. Kimchi A. Schmidt A. Revel M. Isolation of two interferon-induced translational inhibitors: a protein kinase and an oligo-isoadenylate synthetase.Proc. Natl. Acad. Sci. USA. 1978; 75: 4734-4738Crossref PubMed Google Scholar). In theory, any receptor that binds dsRNA could be activated by polyI:C, including further restriction factors, such as ZBP-1 (Z-RNA), although characterizing the specific activity would clearly require multiple gene deletions. This plethora of potential receptors likely contributes to its high toxicity profile, which is reduced in the more selective derivative polyI:C12U (Junt and Barchet, 2015Junt T. Barchet W. Translating nucleic acid-sensing pathways into therapies.Nat. Rev. Immunol. 2015; 15: 529-544Crossref PubMed Scopus (111) Google Scholar).Despite over 50 years of research, many open questions about the molecule’s bioactivity remain: why does low-molecular weight polyI:C (< 300bp) preferentially activate RIG-I given that RIG-I senses the 5′ diphosphate terminus (Goubau et al., 2014Goubau D. Schlee M. Deddouche S. Pruijssers A.J. Zillinger T. Goldeck M. Schuberth C. Van der Veen A.G. Fujimura T. Rehwinkel J. et al.Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5′-diphosphates.Nature. 2014; 514: 372-375Crossref PubMed Scopus (249) Google Scholar)? Why is polyI:C a robust activator of MDA5 while many other defined, long dsRNAs such as poly(A:U) are not (Colby and Chamberlin, 1969Colby C. Chamberlin M.J. The specificity of interferon induction in chick embryo cells by helical RNA.Proc. Natl. Acad. Sci. USA. 1969; 63: 160-167Crossref PubMed Google Scholar; Pichlmair 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 (266) Google Scholar)? Does the mesh-like structure of poly(I:C) contribute to its immune stimulatory activity, as opposed to just its length (Pichlmair 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 (266) Google Scholar)? Why does the polyI:C derivative poly I:C12U (Ampligen) only activate TLR3 but not RIG-I or MDA-5 (Gowen et al., 2007Gowen B.B. Wong M.-H. Jung K.-H. Sanders A.B. Mitchell W.M. Alexopoulou L. Flavell R.A. Sidwell R.W. TLR3 is essential for the induction of protective immunity against Punta Toro Virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not Poly(I:C): differential recognition of synthetic dsRNA molecules.J. Immunol. 2007; 178: 5200-5208Crossref PubMed Google Scholar)?Box 3In vitro Transcription and RIG-I ActivationPhage-encoded DNA-dependent RNA polymerases are commonly used for in-vitro transcription (IVT) of DNA into RNA from linear dsDNA or a plasmid DNA template containing the appropriate promoter sequence (Green and Sambrook, 2020Green M.R. Sambrook J. In Vitro Transcription Systems.Cold Spring Harb. Protoc. 2020; 2020 (Published online January 2, 2020)https://doi.org/10.1101/pdb.top100750Crossref Scopus (1) Google Scholar). This method allows the rapid, cheap, and efficient generation of long RNA molecules, many of which would be prohibitively expensive to produce synthetically. As such, IVT is a popular, often kit-based, method for producing mRNA and CRISPR guide RNA for use with recombinant Cas Proteins. However, since IVT utilizes promoter-based unprimed RNA polymerization, it creates transcripts with a 5′ triphosphate terminus, much like other nascent viral RNA transcripts. We and others used IVT-generated RNA to demonstrate that 5′ triphosphate RNA activated RIG-I (Hornung et" @default.
• W3042281681 created "2020-07-23" @default.
• W3042281681 creator A5063294321 @default.
• W3042281681 creator A5070273513 @default.
• W3042281681 date "2020-07-01" @default.
• W3042281681 modified "2023-10-18" @default.
• W3042281681 title "Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids" @default.
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