ADAR1: "Editor-in-Chief" of Cytoplasmic Innate Immunity

Mart M Lamers, Bernadette G van den Hoogen, Bart L Haagmans, Mart M Lamers, Bernadette G van den Hoogen, Bart L Haagmans

Abstract

Specialized receptors that recognize molecular patterns such as double stranded RNA duplexes-indicative of viral replication-are potent triggers of the innate immune system. Although their activation is beneficial during viral infection, RNA transcribed from endogenous mobile genetic elements may also act as ligands potentially causing autoimmunity. Recent advances indicate that the adenosine deaminase ADAR1 through RNA editing is involved in dampening the canonical antiviral RIG-I-like receptor-, PKR-, and OAS-RNAse L pathways to prevent autoimmunity. However, this inhibitory effect must be overcome during viral infections. In this review we discuss ADAR1's critical role in balancing immune activation and self-tolerance.

Keywords: ADAR1; MDA5; OAS; PKR; RIG-I; cytoplasmic innate immunity.

Figures

Figure 1
Figure 1
The domain architecture of ADAR1 isoforms p150 and p110. NES, nuclear export signal; dsRBD, double-stranded RNA binding domain; NLS, nuclear localization signal.
Figure 2
Figure 2
ADAR1's dampening effect on immune activity prevents autoimmunity in steady-state, but should be regulated during viral infection.
Figure 3
Figure 3
ADAR1 balances self-tolerance and immune activity by modulating canonical antiviral pathways induced by dsRNA. (A) Adenosine to inosine editing or binding of the cytoplasmic ADAR1 isoform p150 or the nuclear p110 to extended dsRNA duplexes prevents their detection by cytoplasmic antiviral signaling pathways, including RIG-I like receptor-, OAS/RNAseL-, and PKR pathways. These dsRNA duplexes can be of viral origin, but in the absence of ADAR1 (B) endogenous dsRNAs—which are likely to originate from inverted Alu repeats or other sources (e.g., mitochondrial dsRNAs)—can also serve as a substrate for antiviral signaling, leading to immune activation, and possibly autoimmunity. Blocking the activation of these pathways prevents IFN-I production, translation arrest, and apoptosis, but this must be tightly regulated in order to not create an environment that favors virus replication.

References

    1. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. . The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. (2004) 5:730–7. 10.1038/ni1087
    1. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, et al. . Cell type-specific involvement of RIG-I in antiviral response. Immunity. (2005) 23:19–28. 10.1016/j.immuni.2005.04.010
    1. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, et al. . Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. (2005) 175:2851–8. 10.4049/jimmunol.175.5.2851
    1. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, et al. . IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol. (2003) 4:491–6. 10.1038/ni921
    1. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. . IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. (2005) 6:981–8. 10.1038/ni1243
    1. Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, et al. . Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. (2000) 13:539–48. 10.1016/S1074-7613(00)00053-4
    1. Dhir A, Dhir S, Borowski LS, Jimenez L, Teitell M, Rotig A, et al. . Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature. (2018) 560:238–42. 10.1038/s41586-018-0363-0
    1. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. (2010) 140:805–20. 10.1016/j.cell.2010.01.022
    1. Basilio C, Wahba AJ, Lengyel P, Speyer JF, Ochoa S. Synthetic polynucleotides and the amino acid code. V Proc Natl Acad Sci USA. (1962) 48:613–6. 10.1073/pnas.48.4.613
    1. Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. (2010) 79:321–49. 10.1146/annurev-biochem-060208-105251
    1. Masquida B, Westhof E. On the wobble GoU and related pairs. RNA. (2000) 6:9–15. 10.1017/S1355838200992082
    1. Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, et al. . Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat Genet. (2012) 44:1243–8. 10.1038/ng.2414
    1. Mannion NM, Greenwood SM, Young R, Cox S, Brindle J, Read D, et al. . The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. (2014) 9:1482–94. 10.1016/j.celrep.2014.10.041
    1. Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, et al. . Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. (2015) 167A:296–312. 10.1002/ajmg.a.36887
    1. Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, et al. . RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science. (2015) 349:1115–20. 10.1126/science.aac7049
    1. Pestal K, Funk CC, Snyder JM, Price ND, Treuting PM, Stetson DB. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity. (2015) 43:933–44. 10.1016/j.immuni.2015.11.001
    1. Samuel CE. Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA-triggered innate immune responses. J Biol Chem. (2019) 294:1710–20. 10.1074/jbc.TM118.004166
    1. Bass BL, Weintraub H. A developmentally regulated activity that unwinds RNA duplexes. Cell. (1987) 48:607–13. 10.1016/0092-8674(87)90239-X
    1. Rebagliati MR, Melton DA. Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell. (1987) 48:599–605. 10.1016/0092-8674(87)90238-8
    1. Bass BL, Weintraub H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell. (1988) 55:1089–98. 10.1016/0092-8674(88)90253-X
    1. Wagner RW, Nishikura K. Cell cycle expression of RNA duplex unwindase activity in mammalian cells. Mol Cell Biol. (1988) 8:770–7. 10.1128/MCB.8.2.770
    1. Wagner RW, Smith JE, Cooperman BS, Nishikura K. A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs. Proc Natl Acad Sci USA. (1989) 86:2647–51. 10.1073/pnas.86.8.2647
    1. Hough RF, Bass BL. Purification of the Xenopus laevis double-stranded RNA adenosine deaminase. J Biol Chem. (1994) 269:9933–9.
    1. Kim U, Wang Y, Sanford T, Zeng Y, Nishikura K. Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc Natl Acad Sci USA. (1994) 91:11457–61. 10.1073/pnas.91.24.11457
    1. Bass BL. RNA editing and hypermutation by adenosine deamination. Trends Biochem Sci. (1997) 22:157–62. 10.1016/S0968-0004(97)01035-9
    1. Bass BL. RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem. (2002) 71:817–46. 10.1146/annurev.biochem.71.110601.135501
    1. Maas S, Rich A, Nishikura K. A-to-I RNA editing: recent news and residual mysteries. J Biol Chem. (2003) 278:1391–4. 10.1074/jbc.R200025200
    1. George CX, Gan Z, Liu Y, Samuel CE. Adenosine deaminases acting on RNA, RNA editing, and interferon action. J Interferon Cytokine Res. (2011) 31:99–117. 10.1089/jir.2010.0097
    1. Melcher T, Maas S, Herb A, Sprengel R, Seeburg PH, Higuchi M. A mammalian RNA editing enzyme. Nature. (1996) 379:460–4. 10.1038/379460a0
    1. Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The genotype-tissue expression (GTEx) project. Nat Genet. (2013) 45:580–5. 10.1038/ng.2653
    1. Melcher T, Maas S, Herb A, Sprengel R, Higuchi M, Seeburg PH. RED2, a brain-specific member of the RNA-specific adenosine deaminase family. J Biol Chem. (1996) 271:31795–8. 10.1074/jbc.271.50.31795
    1. Chen CX, Cho DS, Wang Q, Lai F, Carter KC, Nishikura K. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA. (2000) 6:755–67. 10.1017/S1355838200000170
    1. George CX, Samuel CE. Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc Natl Acad Sci USA. (1999) 96:4621–6. 10.1073/pnas.96.8.4621
    1. Poulsen H, Nilsson J, Damgaard CK, Egebjerg J, Kjems J. CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol Cell Biol. (2001) 21:7862–71. 10.1128/MCB.21.22.7862-7871.2001
    1. Patterson JB, Samuel CE. Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol. (1995) 15:5376–88. 10.1128/MCB.15.10.5376
    1. Eckmann CR, Neunteufl A, Pfaffstetter L, Jantsch MF. The human but not the Xenopus RNA-editing enzyme ADAR1 has an atypical nuclear localization signal and displays the characteristics of a shuttling protein. Mol Biol Cell. (2001) 12:1911–24. 10.1091/mbc.12.7.1911
    1. Strehblow A, Hallegger M, Jantsch MF. Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by double-stranded RNA-binding domains, a leucine-rich export signal, and a putative dimerization domain. Mol Biol Cell. (2002) 13:3822–35. 10.1091/mbc.e02-03-0161
    1. Desterro JM, Keegan LP, Lafarga M, Berciano MT, O'Connell M, Carmo-Fonseca M. Dynamic association of RNA-editing enzymes with the nucleolus. J Cell Sci. (2003) 116:1805–18. 10.1242/jcs.00371
    1. Barraud P, Banerjee S, Mohamed WI, Jantsch MF, Allain FH. A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1. Proc Natl Acad Sci USA. (2014) 111:E1852–61. 10.1073/pnas.1323698111
    1. Patterson JB, Thomis DC, Hans SL, Samuel CE. Mechanism of interferon action: double-stranded RNA-specific adenosine deaminase from human cells is inducible by alpha and gamma interferons. Virology. (1995) 210:508–11. 10.1006/viro.1995.1370
    1. Wang Q, Khillan J, Gadue P, Nishikura K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science. (2000) 290:1765–8. 10.1126/science.290.5497.1765
    1. Hartner JC, Schmittwolf C, Kispert A, Muller AM, Higuchi M, Seeburg PH. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem. (2004) 279:4894–902. 10.1074/jbc.M311347200
    1. Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ, et al. . Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem. (2004) 279:4952–61. 10.1074/jbc.M310162200
    1. Hartner JC, Walkley CR, Lu J, Orkin SH. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol. (2009) 10:109–15. 10.1038/ni.1680
    1. Yang S, Deng P, Zhu Z, Zhu J, Wang G, Zhang L, et al. . Adenosine deaminase acting on RNA 1 limits RIG-I RNA detection and suppresses IFN production responding to viral and endogenous RNAs. J Immunol. (2014) 193:3436–45. 10.4049/jimmunol.1401136
    1. Wang H, Wang G, Zhang L, Zhang J, Zhang J, Wang Q, et al. . ADAR1 suppresses the activation of cytosolic RNA-sensing signaling pathways to protect the liver from ischemia/reperfusion injury. Sci Rep. (2016) 6:20248. 10.1038/srep20248
    1. Pujantell M, Riveira-Munoz E, Badia R, Castellvi M, Garcia-Vidal E, Sirera G, et al. . RNA editing by ADAR1 regulates innate and antiviral immune functions in primary macrophages. Sci Rep. (2017) 7:13339. 10.1038/s41598-017-13580-0
    1. Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. (1984) 15:49–54. 10.1002/ana.410150109
    1. Lebon P, Badoual J, Ponsot G, Goutieres F, Hemeury-Cukier F, Aicardi J. Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy. J Neurol Sci. (1988) 84:201–8. 10.1016/0022-510X(88)90125-6
    1. Bonnemann CG, Meinecke P. Encephalopathy of infancy with intracerebral calcification and chronic spinal fluid lymphocytosis–another case of the Aicardi-Goutieres syndrome. Neuropediatrics. (1992) 23:157–61. 10.1055/s-2008-1071333
    1. Rice GI, Forte GM, Szynkiewicz M, Chase DS, Aeby A, Abdel-Hamid MS, et al. . Assessment of interferon-related biomarkers in Aicardi-Goutieres syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study. Lancet Neurol. (2013) 12:1159–69. 10.1016/S1474-4422(13)70258-8
    1. Oda H, Nakagawa K, Abe J, Awaya T, Funabiki M, Hijikata A, et al. . Aicardi-Goutieres syndrome is caused by IFIH1 mutations. Am J Hum Genet. (2014) 95:121–5. 10.1016/j.ajhg.2014.06.007
    1. Rice GI, Del Toro Duany Y, Jenkinson EM, Forte GM, Anderson BH, Ariaudo G, et al. . Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. (2014) 46:503–9. 10.1038/ng.2933
    1. Ahmad S, Mu X, Yang F, Greenwald E, Park JW, Jacob E, et al. . Breaching self-tolerance to alu duplex RNA underlies MDA5-mediated inflammation. Cell. (2018) 172:797–810 e713. 10.1016/j.cell.2017.12.016
    1. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. . Initial sequencing and analysis of the human genome. Nature. (2001) 409:860–921. 10.1038/35057062
    1. Wahlstedt H, Ohman M. Site-selective versus promiscuous A-to-I editing. Wiley Interdiscip Rev RNA. (2011) 2:761–71. 10.1002/wrna.89
    1. Athanasiadis A, Rich A, Maas S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. (2004) 2:e391. 10.1371/journal.pbio.0020391
    1. Blow M, Futreal PA, Wooster R, Stratton MR. A survey of RNA editing in human brain. Genome Res. (2004) 14:2379–87. 10.1101/gr.2951204
    1. Kim DD, Kim TT, Walsh T, Kobayashi Y, Matise TC, Buyske S, et al. . Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. (2004) 14:1719–25. 10.1101/gr.2855504
    1. Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, et al. . Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol. (2004) 22:1001–5. 10.1038/nbt996
    1. Li JB, Levanon EY, Yoon JK, Aach J, Xie B, Leproust E, et al. . Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science. (2009) 324:1210–3. 10.1126/science.1170995
    1. Sakurai M, Yano T, Kawabata H, Ueda H, Suzuki T. Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. Nat Chem Biol. (2010) 6:733–40. 10.1038/nchembio.434
    1. Peng Z, Cheng Y, Tan BC, Kang L, Tian Z, Zhu Y, et al. . Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat Biotechnol. (2012) 30:253–60. 10.1038/nbt.2122
    1. Ramaswami G, Lin W, Piskol R, Tan MH, Davis C, Li JB. Accurate identification of human Alu and non-Alu RNA editing sites. Nat Methods. (2012) 9:579–81. 10.1038/nmeth.1982
    1. Ramaswami G, Zhang R, Piskol R, Keegan LP, Deng P, O'Connell MA, et al. . Identifying RNA editing sites using RNA sequencing data alone. Nat Methods. (2013) 10:128–32. 10.1038/nmeth.2330
    1. Bazak L, Haviv A, Barak M, Jacob-Hirsch J, Deng P, Zhang R, et al. . A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res. (2014) 24:365–76. 10.1101/gr.164749.113
    1. Porath HT, Carmi S, Levanon EY. A genome-wide map of hyper-edited RNA reveals numerous new sites. Nat Commun. (2014) 5:4726. 10.1038/ncomms5726
    1. Fumagalli D, Gacquer D, Rothe F, Lefort A, Libert F, Brown D, et al. . Principles governing A-to-I RNA editing in the breast cancer transcriptome. Cell Rep. (2015) 13:277–89. 10.1016/j.celrep.2015.09.032
    1. Han L, Diao L, Yu S, Xu X, Li J, Zhang R, et al. . The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell. (2015) 28:515–28. 10.1016/j.ccell.2015.08.013
    1. Paz-Yaacov N, Bazak L, Buchumenski I, Porath HT, Danan-Gotthold M, Knisbacher BA, et al. . Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep. (2015) 13:267–76. 10.1016/j.celrep.2015.08.080
    1. Chung H, Calis JJA, Wu X, Sun T, Yu Y, Sarbanes SL, et al. . Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell. (2018) 172:811–24 e814. 10.1016/j.cell.2017.12.038
    1. Liddicoat BJ, Chalk AM, Walkley CR. ADAR1, inosine and the immune sensing system: distinguishing self from non-self. Wiley Interdiscip Rev RNA. (2016) 7:157–72. 10.1002/wrna.1322
    1. Vitali P, Scadden AD. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat Struct Mol Biol. (2010) 17:1043–50. 10.1038/nsmb.1864
    1. Dauber B, Wolff T. Activation of the antiviral kinase PKR and viral countermeasures. Viruses. (2009) 1:523–44. 10.3390/v1030523
    1. Ung TL, Cao C, Lu J, Ozato K, Dever TE. Heterologous dimerization domains functionally substitute for the double-stranded RNA binding domains of the kinase PKR. EMBO J. (2001) 20:3728–37. 10.1093/emboj/20.14.3728
    1. Zhang F, Romano PR, Nagamura-Inoue T, Tian B, Dever TE, Mathews MB, et al. . Binding of double-stranded RNA to protein kinase PKR is required for dimerization and promotes critical autophosphorylation events in the activation loop. J Biol Chem. (2001) 276:24946–58. 10.1074/jbc.M102108200
    1. Dar AC, Dever TE, Sicheri F. Higher-order substrate recognition of eIF2alpha by the RNA-dependent protein kinase PKR. Cell. (2005) 122:887–900. 10.1016/j.cell.2005.06.044
    1. Dey M, Cao C, Dar AC, Tamura T, Ozato K, Sicheri F, et al. . Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell. (2005) 122:901–13. 10.1016/j.cell.2005.06.041
    1. Farrell PJ, Sen GC, Dubois MF, 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) 75:5893–7. 10.1073/pnas.75.12.5893
    1. Levin D, London IM. 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) 75:1121–5. 10.1073/pnas.75.3.1121
    1. Nie Y, Hammond GL, Yang JH. Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus infection. J Virol. (2007) 81:917–23. 10.1128/JVI.01527-06
    1. Clerzius G, Gelinas JF, Daher A, Bonnet M, Meurs EF, Gatignol A. ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication. J Virol. (2009) 83:10119–28. 10.1128/JVI.02457-08
    1. Toth AM, Li Z, Cattaneo R, Samuel CE. RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR. J Biol Chem. (2009) 284:29350–6. 10.1074/jbc.M109.045146
    1. Wang Y, Samuel CE. Adenosine deaminase ADAR1 increases gene expression at the translational level by decreasing protein kinase PKR-dependent eIF-2alpha phosphorylation. J Mol Biol. (2009) 393:777–87. 10.1016/j.jmb.2009.08.070
    1. Li Z, Wolff KC, Samuel CE. RNA adenosine deaminase ADAR1 deficiency leads to increased activation of protein kinase PKR and reduced vesicular stomatitis virus growth following interferon treatment. Virology. (2010) 396:316–22. 10.1016/j.virol.2009.10.026
    1. John L, Samuel CE. Induction of stress granules by interferon and down-regulation by the cellular RNA adenosine deaminase ADAR1. Virology. (2014). 454–5:299–310. 10.1016/j.virol.2014.02.025
    1. Phuphuakrat A, Kraiwong R, Boonarkart C, Lauhakirti D, Lee TH, Auewarakul P. Double-stranded RNA adenosine deaminases enhance expression of human immunodeficiency virus type 1 proteins. J Virol. (2008) 82:10864–72. 10.1128/JVI.00238-08
    1. Doria M, Neri F, Gallo A, Farace MG, Michienzi A. Editing of HIV-1 RNA by the double-stranded RNA deaminase ADAR1 stimulates viral infection. Nucleic Acids Res. (2009) 37:5848–58. 10.1093/nar/gkp604
    1. Okonski KM, Samuel CE. Stress granule formation induced by measles virus is protein kinase PKR dependent and impaired by RNA adenosine deaminase ADAR1. J Virol. (2013) 87:756–66. 10.1128/JVI.02270-12
    1. Ng CS, Jogi M, Yoo JS, Onomoto K, Koike S, Iwasaki T, et al. . Encephalomyocarditis virus disrupts stress granules, the critical platform for triggering antiviral innate immune responses. J Virol. (2013) 87:9511–22. 10.1128/JVI.03248-12
    1. Pfaller CK, Li Z, George CX, Samuel CE. Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response. Curr Opin Immunol. (2011) 23:573–82. 10.1016/j.coi.2011.08.009
    1. Zamanian-Daryoush M, Mogensen TH, DiDonato JA, Williams BR. NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase. Mol Cell Biol. (2000) 20:1278–90. 10.1128/MCB.20.4.1278-1290.2000
    1. Gil J, Garcia MA, Gomez-Puertas P, Guerra S, Rullas J, Nakano H, et al. . TRAF family proteins link PKR with NF-kappa B activation. Mol Cell Biol. (2004) 24:4502–12. 10.1128/MCB.24.10.4502-4512.2004
    1. Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schafer R, Kumar A, et al. . Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. (1995) 14:6095–106. 10.1002/j.1460-2075.1995.tb00300.x
    1. Smith EJ, Marie I, Prakash A, Garcia-Sastre A, Levy DE. IRF3 and IRF7 phosphorylation in virus-infected cells does not require double-stranded RNA-dependent protein kinase R or Ikappa B kinase but is blocked by Vaccinia virus E3L protein. J Biol Chem. (2001) 276:8951–7. 10.1074/jbc.M008717200
    1. Diebold SS, Montoya M, Unger H, Alexopoulou L, Roy P, Haswell LE, et al. . Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature. (2003) 424:324–8. 10.1038/nature01783
    1. McAllister CS, Samuel CE. The RNA-activated protein kinase enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors. J Biol Chem. (2009) 284:1644–51. 10.1074/jbc.M807888200
    1. Carpentier PA, Williams BR, Miller SD. Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli. Glia. (2007) 55:239–52. 10.1002/glia.20450
    1. Gilfoy FD, Mason PW. West Nile virus-induced interferon production is mediated by the double-stranded RNA-dependent protein kinase PKR. J Virol. (2007) 81:11148–58. 10.1128/JVI.00446-07
    1. Barry G, Breakwell L, Fragkoudis R, Attarzadeh-Yazdi G, Rodriguez-Andres J, Kohl A, et al. . PKR acts early in infection to suppress Semliki Forest virus production and strongly enhances the type I interferon response. J Gen Virol. (2009) 90:1382–91. 10.1099/vir.0.007336-0
    1. McAllister CS, Toth AM, Zhang P, Devaux P, Cattaneo R, Samuel CE. Mechanisms of protein kinase PKR-mediated amplification of beta interferon induction by C protein-deficient measles virus. J Virol. (2010) 84:380–6. 10.1128/JVI.02630-08
    1. Schulz O, Pichlmair A, Rehwinkel J, Rogers NC, Scheuner D, Kato H, et al. . Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe. (2010) 7:354–61. 10.1016/j.chom.2010.04.007
    1. Pham AM, Santa Maria FG, Lahiri T, Friedman E, Marie IJ, Levy DE. PKR Transduces MDA5-dependent signals for Type I IFN induction. PLoS Pathog. (2016) 12:e1005489. 10.1371/journal.ppat.1005489
    1. Dong B, Silverman RH. 2-5A-dependent RNase molecules dimerize during activation by 2-5A. J Biol Chem. (1995) 270:4133–7. 10.1074/jbc.270.8.4133
    1. Wreschner DH, McCauley JW, Skehel JJ, Kerr IM. Interferon action–sequence specificity of the ppp(A2'p)nA-dependent ribonuclease. Nature. (1981) 289:414–7. 10.1038/289414a0
    1. Wreschner DH, James TC, Silverman RH, Kerr IM. Ribosomal RNA cleavage, nuclease activation and 2-5A(ppp(A2'p)nA) in interferon-treated cells. Nucleic Acids Res. (1981) 9:1571–81. 10.1093/nar/9.7.1571
    1. Chakrabarti A, Ghosh PK, Banerjee S, Gaughan C, Silverman RH. RNase L triggers autophagy in response to viral infections. J Virol. (2012) 86:11311–21. 10.1128/JVI.00270-12
    1. Siddiqui MA, Malathi K. RNase L induces autophagy via c-Jun N-terminal kinase and double-stranded RNA-dependent protein kinase signaling pathways. J Biol Chem. (2012) 287:43651–64. 10.1074/jbc.M112.399964
    1. Castelli JC, Hassel BA, Wood KA, Li XL, Amemiya K, Dalakas MC, et al. . A study of the interferon antiviral mechanism: apoptosis activation by the 2-5A system. J Exp Med. (1997) 186:967–72. 10.1084/jem.186.6.967
    1. Zhou A, Paranjape J, Brown TL, Nie H, Naik S, Dong B, et al. . Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase L. EMBO J. (1997) 16:6355–63. 10.1093/emboj/16.21.6355
    1. Castelli J, Wood KA, Youle RJ. The 2-5A system in viral infection and apoptosis. Biomed Pharmacother. (1998) 52:386–90. 10.1016/S0753-3322(99)80006-7
    1. Li Y, Banerjee S, Goldstein SA, Dong B, Gaughan C, Rath S, et al. . Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line. Elife. (2017) 6:e25687. 10.7554/eLife.25687
    1. Samuel CE. Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral. Virology. (2011) 411:180–93. 10.1016/j.virol.2010.12.004
    1. Ohara PJ, Nichol ST, Horodyski FM, Holland JJ. Vesicular stomatitis-virus defective interfering particles can contain extensive genomic sequence rearrangements and base substitutions. Cell. (1984) 36:915–24. 10.1016/0092-8674(84)90041-2
    1. Cattaneo R, Schmid A, Eschle D, Baczko K, Termeulen V, Billeter MA. Biased hypermutation and other genetic changes in defective measles viruses in human-brain infections. Cell. (1988) 55:255–65. 10.1016/0092-8674(88)90048-7
    1. van den Hoogen BG, van Boheemen S, de Rijck J, van Nieuwkoop S, Smith DJ, Laksono B, et al. . Excessive production and extreme editing of human metapneumovirus defective interfering RNA is associated with type I IFN induction. J Gen Virol. (2014) 95:1625–33. 10.1099/vir.0.066100-0
    1. Kitajewski J, Schneider RJ, Safer B, Munemitsu SM, Samuel CE, Thimmappaya B, et al. . Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 alpha kinase. Cell. (1986) 45:195–200. 10.1016/0092-8674(86)90383-1
    1. Mori K, Juttermann R, Wienhues U, Kobayashi K, Yagi M, Sugimoto T, et al. . Anti-interferon activity of adenovirus-2-encoded VAI and VAII RNAs in translation in cultured human cells. Virus Res. (1996) 42:53–63. 10.1016/0168-1702(95)01309-1
    1. Lei M, Liu Y, Samuel CE. Adenovirus VAI RNA antagonizes the RNA-editing activity of the ADAR adenosine deaminase. Virology. (1998) 245:188–96. 10.1006/viro.1998.9162
    1. Katze MG, DeCorato D, Safer B, Galabru J, Hovanessian AG. Adenovirus VAI RNA complexes with the 68 000 Mr protein kinase to regulate its autophosphorylation and activity. EMBO J. (1987) 6:689–97. 10.1002/j.1460-2075.1987.tb04809.x
    1. Liu Y, Wolff KC, Jacobs BL, Samuel CE. Vaccinia virus E3L interferon resistance protein inhibits the interferon-induced adenosine deaminase A-to-I editing activity. Virology. (2001) 289:378–87. 10.1006/viro.2001.1154
    1. Chang HW, Watson JC, Jacobs BL. The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci USA. (1992) 89:4825–9. 10.1073/pnas.89.11.4825
    1. de Chassey B, Aublin-Gex A, Ruggieri A, Meyniel-Schicklin L, Pradezynski F, Davoust N, et al. . The interactomes of influenza virus NS1 and NS2 proteins identify new host factors and provide insights for ADAR1 playing a supportive role in virus replication. PLoS Pathog. (2013) 9:e1003440. 10.1371/journal.ppat.1003440
    1. Fritzell K, Xu LD, Lagergren J, Ohman M. ADARs and editing: the role of A-to-I RNA modification in cancer progression. Semin Cell Dev Biol. (2018) 79:123–30. 10.1016/j.semcdb.2017.11.018
    1. Bhate A, Sun T, Li JB. ADAR1: a new target for immuno-oncology therapy. Mol Cell. (2019) 73:866–8. 10.1016/j.molcel.2019.02.021
    1. Chen L, Li Y, Lin CH, Chan TH, Chow RK, Song Y, et al. . Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med. (2013) 19:209–16. 10.1038/nm.3043
    1. Qin YR, Qiao JJ, Chan TH, Zhu YH, Li FF, Liu H, et al. . Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. Cancer Res. (2014) 74:840–51. 10.1158/0008-5472.CAN-13-2545
    1. Hu X, Wan S, Ou Y, Zhou B, Zhu J, Yi X, et al. . RNA over-editing of BLCAP contributes to hepatocarcinogenesis identified by whole-genome and transcriptome sequencing. Cancer Lett. (2015) 357:510–9. 10.1016/j.canlet.2014.12.006
    1. Chen Y, Wang H, Lin W, Shuai P. ADAR1 overexpression is associated with cervical cancer progression and angiogenesis. Diagn Pathol. (2017) 12:12. 10.1186/s13000-017-0600-0
    1. Yang WD, Chendrimada TP, Wang QD, Higuchi M, Seeburg PH, Shiekhattar R, et al. . Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol. (2006) 13:13–21. 10.1038/nsmb1041
    1. Kawahara Y, Megraw M, Kreider E, Iizasa H, Valente L, Hatzigeorgiou AG, et al. . Frequency and fate of microRNA editing in human brain. Nucleic Acids Res. (2008) 36:5270–80. 10.1093/nar/gkn479
    1. Zipeto MA, Court AC, Sadarangani A, Delos Santos NP, Balaian L, Chun HJ, et al. . ADAR1 activation drives leukemia stem cell self-renewal by impairing Let-7 biogenesis. Cell Stem Cell. (2016) 19:177–91. 10.1016/j.stem.2016.05.004
    1. Wang Y, Xu X, Yu S, Jeong KJ, Zhou Z, Han L, et al. . Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers. Genome Res. (2017) 27:1112–25. 10.1101/gr.219741.116
    1. Ota H, Sakurai M, Gupta R, Valente L, Wulff BE, Ariyoshi K, et al. . ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell. (2013) 153:575–89. 10.1016/j.cell.2013.03.024
    1. Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. (2016) 16:131–44. 10.1038/nrc.2016.14
    1. Matveeva OV, Chumakov PM. Defects in interferon pathways as potential biomarkers of sensitivity to oncolytic viruses. Rev Med Virol. (2018) 28:e2008. 10.1002/rmv.2008
    1. Gannon HS, Zou T, Kiessling MK, Gao GF, Cai D, Choi PS, et al. . Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun. (2018) 9:5450. 10.1038/s41467-018-07824-4
    1. Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, Iracheta-Vellve A, et al. . Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature. (2019) 565:43–8. 10.1038/s41586-018-0768-9
    1. Liu H, Golji J, Brodeur LK, Chung FS, Chen JT, deBeaumont RS, et al. . Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat Med. (2019) 25:95–102. 10.1038/s41591-018-0302-5
    1. Carone DM, Lawrence JB. Heterochromatin instability in cancer: from the Barr body to satellites and the nuclear periphery. Semin Cancer Biol. (2013) 23:99–108. 10.1016/j.semcancer.2012.06.008
    1. Levine AJ, Ting DT, Greenbaum BD. P53 and the defenses against genome instability caused by transposons and repetitive elements. Bioessays. (2016) 38:508–13. 10.1002/bies.201600031
    1. Wylie A, Jones AE, D'Brot A, Lu WJ, Kurtz P, Moran JV, et al. . p53 genes function to restrain mobile elements. Genes Dev. (2016) 30:64–77. 10.1101/gad.266098.115
    1. Cho DS, Yang W, Lee JT, Shiekhattar R, Murray JM, Nishikura K. Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J Biol Chem. (2003) 278:17093–102. 10.1074/jbc.M213127200
    1. Gallo A, Keegan LP, Ring GM, O'Connell MA. An ADAR that edits transcripts encoding ion channel subunits functions as a dimer. EMBO J. (2003) 22:3421–30. 10.1093/emboj/cdg327
    1. Doyle M, Jantsch MF. New and old roles of the double-stranded RNA-binding domain. J Struct Biol. (2002) 140:147–53. 10.1016/S1047-8477(02)00544-0
    1. Desterro JM, Keegan LP, Jaffray E, Hay RT, O'Connell MA, Carmo-Fonseca M. SUMO-1 modification alters ADAR1 editing activity. Mol Biol Cell. (2005) 16:5115–26. 10.1091/mbc.e05-06-0536
    1. Li L, Qian G, Zuo Y, Yuan Y, Cheng Q, Guo T, et al. . Ubiquitin-dependent turnover of adenosine deaminase acting on RNA 1 (ADAR1) is required for efficient antiviral activity of type I interferon. J Biol Chem. (2016) 291:24974–85. 10.1074/jbc.M116.737098
    1. Macbeth MR, Schubert HL, Vandemark AP, Lingam AT, Hill CP, Bass BL. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science. (2005) 309:1534–9. 10.1126/science.1113150
    1. Pulloor NK, Nair S, Kostic AD, Bist P, Weaver JD, Riley AM, et al. . Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in type-I interferon response. Plos Pathog. (2014) 10:e1003981. 10.1371/journal.ppat.1003981
    1. Knisbacher BA, Levanon EY. DNA and RNA editing of retrotransposons accelerate mammalian genome evolution. Ann N Y Acad Sci. (2015) 1341:115–25. 10.1111/nyas.12713

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj