1932

Abstract

The innate immune system utilizes pattern-recognition receptors (PRRs) to detect the invasion of pathogens and initiate host antimicrobial responses such as the production of type I interferons and proinflammatory cytokines. Nucleic acids, which are essential genetic information carriers for all living organisms including viral, bacterial, and eukaryotic pathogens, are major structures detected by the innate immune system. However, inappropriate detection of self nucleic acids can result in autoimmune diseases. PRRs that recognize nucleic acids in cells include several endosomal members of the Toll-like receptor family and several cytosolic sensors for DNA and RNA. Here, we review the recent advances in understanding the mechanism of nucleic acid sensing and signaling in the cytosol of mammalian cells as well as the emerging role of cytosolic nucleic acids in autoimmunity.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-032713-120156
2014-03-21
2024-04-17
Loading full text...

Full text loading...

/deliver/fulltext/immunol/32/1/annurev-immunol-032713-120156.html?itemId=/content/journals/10.1146/annurev-immunol-032713-120156&mimeType=html&fmt=ahah

Literature Cited

  1. Kawai T, Akira S. 1.  2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–50 [Google Scholar]
  2. Ablasser A, Hertrich C, Waßermann R, Hornung V. 2.  2013. Nucleic acid driven sterile inflammation. Clin. Immunol. 147:207–15 [Google Scholar]
  3. Platanias LC. 3.  2005. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5:375–86 [Google Scholar]
  4. Silverman N, Maniatis T. 4.  2001. NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15:2321–42 [Google Scholar]
  5. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E. 5.  et al. 2003. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4:491–96 [Google Scholar]
  6. Sharma S, tenOever BR, Grandvaux N, Zhou G-P, Lin R, Hiscott J. 6.  2003. Triggering the interferon antiviral response through an IKK-related pathway. Science 300:1148–51 [Google Scholar]
  7. Honda K, Taniguchi T. 7.  2006. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6:644–58 [Google Scholar]
  8. Kawai T, Akira S. 8.  2010. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11:373–84 [Google Scholar]
  9. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. 9.  2001. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732–38 [Google Scholar]
  10. Negishi H, Osawa T, Ogami K, Ouyang X, Sakagushi S. 10.  et al. 2008. A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. Proc. Natl. Acad. Sci. USA 105:20446–51 [Google Scholar]
  11. Akira S, Uematsu S, Takeuchi O. 11.  2006. Pathogen recognition and innate immunity. Cell 124:783–801 [Google Scholar]
  12. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. 12.  2004. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–31 [Google Scholar]
  13. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C. 13.  et al. 2004. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303:1526–29 [Google Scholar]
  14. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H. 14.  et al. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3:196–200 [Google Scholar]
  15. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S. 15.  et al. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740–45 [Google Scholar]
  16. Li X-D, Chen ZJ. 16.  2012. Sequence specific detection of bacterial 23S ribosomal RNA by TLR13. eLife 1:300102 [Google Scholar]
  17. Oldenburg M, Krüger A, Ferstl R, Kaufmann A, Nees G. 17.  et al. 2012. TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance–forming modification. Science 337:1111–15 [Google Scholar]
  18. Goubau D, Deddouche S, Reis e Sousa C. 18.  2013. Cytosolic sensing of viruses. Immunity 38:855–69 [Google Scholar]
  19. Diebold SS, Montoya M, Unger H, Alexopoulou L, Roy P. 19.  et al. 2003. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424:324–28 [Google Scholar]
  20. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T. 20.  et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5:730–37 [Google Scholar]
  21. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M. 21.  et al. 2005. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175:2851–58 [Google Scholar]
  22. Kolakofsky D, Kowalinski E, Cusack S. 22.  2012. A structure-based model of RIG-I activation. RNA 18:2118–27 [Google Scholar]
  23. Luo D, Kohlway A, Pyle AM. 23.  2013. Duplex RNA activated ATPases (DRAs): platforms for RNA sensing, signaling and processing. RNA Biol. 10:111–20 [Google Scholar]
  24. Jiang X, Kinch LN, Brautigam CA, Chen X, Du F. 24.  et al. 2012. Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates antiviral innate immune response. Immunity 36:959–73 [Google Scholar]
  25. Yoneyama M, Fujita T. 25.  2010. Recognition of viral nucleic acids in innate immunity. Rev. Med. Virol. 20:4–22 [Google Scholar]
  26. Venkataraman T, Valdes M, Elsby R, Kakuta S, Caceres G. 26.  et al. 2007. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J. Immunol. 178:6444–55 [Google Scholar]
  27. Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S. 27.  et al. 2010. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc. Natl. Acad. Sci. USA 107:1512–17 [Google Scholar]
  28. Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B. 28.  et al. 2006. Essential role of MDA5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA 103:8459–64 [Google Scholar]
  29. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M. 29.  et al. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–5 [Google Scholar]
  30. Fredericksen BL, Keller BC, Fornek J, Katze MG, Gale M. 30.  2008. Establishment and maintenance of the innate antiviral response to West Nile virus involves both RIG-I and MDA5 signaling through IPS-1. J. Virol. 82:609–16 [Google Scholar]
  31. Loo Y-M, Fornek J, Crochet N, Bajwa G, Perwitasari O. 31.  et al. 2008. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J. Virol. 82:335–45 [Google Scholar]
  32. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T. 32.  et al. 2008. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid–inducible gene-I and melanoma differentiation–associated gene 5. J. Exp. Med. 205:1601–10 [Google Scholar]
  33. Hornung V, Ellegast J, Kim S, Brzózka K, Jung A. 33.  et al. 2006. 5′-triphosphate RNA is the ligand for RIG-I. Science 314:994–97 [Google Scholar]
  34. Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P. 34.  et al. 2006. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314:997–1001 [Google Scholar]
  35. Schlee M, Roth A, Hornung V, Hagmann CA, Wimmenauer V. 35.  et al. 2009. Recognition of 52 triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 31:25–34 [Google Scholar]
  36. Schmidt A, Schwerd T, Hamm W, Hellmuth JC, Cui S. 36.  et al. 2009. 5′-triphosphate RNA requires base-paired structures to activate antiviral signaling via RIG-I. Proc. Natl. Acad. Sci. USA 106:12067–72 [Google Scholar]
  37. Malathi K, Dong B, Gale M, Silverman RH. 37.  2007. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448:816–19 [Google Scholar]
  38. Malathi K, Saito T, Crochet N, Barton DJ, Gale M Jr, Silverman RH. 38.  2010. RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP. RNA 16:2108–19 [Google Scholar]
  39. Rehwinkel J, Tan CP, Goubau D, Schulz O, Pichlmair A. 39.  et al. 2010. RIG-I detects viral genomic RNA during negative-strand RNA virus infection. Cell 140:397–408 [Google Scholar]
  40. Baum A, Sachidanandam R, García-Sastre A. 40.  2010. Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc. Natl. Acad. Sci. USA 107:16303–8 [Google Scholar]
  41. Feng Q, Hato SV, Langereis MA, Zoll J, Virgen-Slane R. 41.  et al. 2012. MDA5 detects the double-stranded RNA replicative form in picornavirus-infected cells. Cell Rep. 2:1187–96 [Google Scholar]
  42. Pichlmair A, Schulz O, Tan C-P, Rehwinkel J, Kato H. 42.  et al. 2009. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J. Virol. 83:10761–69 [Google Scholar]
  43. Kowalinski E, Lunardi T, McCarthy AA, Louber J, Brunel J. 43.  et al. 2011. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell 147:423–35 [Google Scholar]
  44. Leung DW, Amarasinghe GK. 44.  2012. Structural insights into RNA recognition and activation of RIG-I-like receptors. Curr. Opin. Struct. Biol. 22:297–303 [Google Scholar]
  45. Jiang F, Ramanathan A, Miller MT, Tang G-Q, Gale M. 45.  et al. 2011. Structural basis of RNA recognition and activation by innate immune receptor RIG-I. Nature 479:423–27 [Google Scholar]
  46. Luo D, Ding SC, Vela A, Kohlway A, Lindenbach BD, Pyle AM. 46.  2011. Structural insights into RNA recognition by RIG-I. Cell 147:409–22 [Google Scholar]
  47. Civril F, Bennett M, Moldt M, Deimling T, Witte G. 47.  et al. 2011. The RIG-I ATPase domain structure reveals insights into ATP-dependent antiviral signalling. EMBO Rep. 12:1127–34 [Google Scholar]
  48. Gack MU, Shin YC, Joo C-H, Urano T, Liang C. 48.  et al. 2007. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446:916–20 [Google Scholar]
  49. Oshiumi H, Matsumoto M, Hatakeyama S, Seya T. 49.  2009. Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-β induction during the early phase of viral infection. J. Biol. Chem. 284:807–17 [Google Scholar]
  50. Oshiumi H, Miyashita M, Inoue N, Okabe M, Matsumoto M, Seya T. 50.  2010. The ubiquitin ligase riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection. Cell Host Microbe 8:496–509 [Google Scholar]
  51. Zeng W, Sun L, Jiang X, Chen X, Hou F. 51.  et al. 2010. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141:315–30 [Google Scholar]
  52. Peisley A, Lin C, Wu B, Orme-Johnson M, Liu M. 52.  et al. 2011. Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc. Natl. Acad. Sci. USA 108:21010–15 [Google Scholar]
  53. Berke IC, Yu X, Modis Y, Egelman EH. 53.  2012. MDA5 assembles into a polar helical filament on dsRNA. Proc. Natl. Acad. Sci. USA 109:18437–41 [Google Scholar]
  54. Berke IC, Modis Y. 54.  2012. MDA5 cooperatively forms dimers and ATP-sensitive filaments upon binding double-stranded RNA. EMBO J. 31:1714–26 [Google Scholar]
  55. Wu B, Peisley A, Richards C, Yao H, Zeng X. 55.  et al. 2013. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152:276–89 [Google Scholar]
  56. Seth RB, Sun L, Ea C-K, Chen ZJ. 56.  2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. Cell 122:669–82 [Google Scholar]
  57. Kawai T, Takahashi K, Sato S, Coban C, Kumar H. 57.  et al. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6:981–88 [Google Scholar]
  58. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M. 58.  et al. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–72 [Google Scholar]
  59. Xu L-G, Wang Y-Y, Han K-J, Li L-Y, Zhai Z, Shu H-B. 59.  2005. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell 19:727–40 [Google Scholar]
  60. Sun Q, Sun L, Liu H-H, Chen X, Seth RB. 60.  et al. 2006. The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24:633–42 [Google Scholar]
  61. Kumar H, Kawai T, Kato H, Sato S, Takahashi K. 61.  et al. 2006. Essential role of IPS-1 in innate immune responses against RNA viruses. J. Exp. Med. 203:1795–803 [Google Scholar]
  62. Hou F, Sun L, Zheng H, Skaug B, Jiang Q-X, Chen ZJ. 62.  2011. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146:448–61 [Google Scholar]
  63. Li X-D, Sun L, Seth RB, Pineda G, Chen ZJ. 63.  2005. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Natl. Acad. Sci. USA 102:17717–22 [Google Scholar]
  64. Castanier C, Garcin D, Vazquez A, Arnoult D. 64.  2010. Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. EMBO Rep. 11:133–38 [Google Scholar]
  65. Onoguchi K, Onomoto K, Takamatsu S, Jogi M, Takemura A. 65.  et al. 2010. Virus-infection or 5′ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1. PLoS Pathog. 6:e1001012 [Google Scholar]
  66. Yasukawa K, Oshiumi H, Takeda M, Ishihara N, Yanagi Y. 66.  et al. 2009. Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci. Signal. 2:ra47 [Google Scholar]
  67. Koshiba T, Yasukawa K, Yanagi Y, Kawabata S-i. 67.  2011. Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling. Sci. Signal. 4:ra7 [Google Scholar]
  68. Ea C-K, Deng L, Xia Z-P, Pineda G, Chen ZJ. 68.  2006. Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 22:245–57 [Google Scholar]
  69. Wu C-J, Conze DB, Li T, Srinivasula SM, Ashwell JD. 69.  2006. Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-κB activation. Nat. Cell Biol. 8:398–406 [Google Scholar]
  70. Zeng W, Xu M, Liu S, Sun L, Chen ZJ. 70.  2009. Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol. Cell 36:315–25 [Google Scholar]
  71. Paz S, Vilasco M, Werden SJ, Arguello M, Joseph-Pillai D. 71.  et al. 2011. A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral response. Cell Res. 21:895–910 [Google Scholar]
  72. Saha SK, Pietras EM, He JQ, Kang JR, Liu S-Y. 72.  et al. 2006. Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J. 25:3257–63 [Google Scholar]
  73. Tang ED, Wang CY. 73.  2010. TRAF5 is a downstream target of MAVS in antiviral innate immune signaling. PLoS ONE 5:e9172 [Google Scholar]
  74. Li S, Wang L, Berman M, Kong Y-Y, Dorf ME. 74.  2011. Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 35:426–40 [Google Scholar]
  75. Mao A-P, Li S, Zhong B, Li Y, Yan J. 75.  et al. 2010. Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-β (IFN-β) and cellular antiviral response. J. Biol. Chem. 285:9470–76 [Google Scholar]
  76. Liu S, Chen J, Cai X, Wu J, Chen X. 76.  et al. 2013. MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. eLife 2:e00785 [Google Scholar]
  77. Oshiumi H, Matsumoto M, Seya T. 77.  2012. Ubiquitin-mediated modulation of the cytoplasmic viral RNA sensor RIG-I. J. Biochem. 151:5–11 [Google Scholar]
  78. Arimoto K-i, Takahashi H, Hishiki T, Konishi H, Fujita T, Shimotohno K. 78.  2007. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc. Natl. Acad. Sci. USA 104:7500–5 [Google Scholar]
  79. Chen W, Han C, Xie B, Hu X, Yu Q. 79.  et al. 2013. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell 152:467–78 [Google Scholar]
  80. Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cardenas WB. 80.  et al. 2008. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep. 9:930–36 [Google Scholar]
  81. Wang L, Zhao W, Zhang M, Wang P, Zhao K. 81.  et al. 2013. USP4 positively regulates RIG-I-mediated antiviral response through deubiquitination and stabilization of RIG-I. J. Virol. 87:4507–15 [Google Scholar]
  82. Gack MU, Nistal-Villán E, Inn K-S, García-Sastre A, Jung JU. 82.  2010. Phosphorylation-mediated negative regulation of RIG-I antiviral activity. J. Virol. 84:3220–29 [Google Scholar]
  83. Nistal-Villán E, Gack MU, Martínez-Delgado G, Maharaj NP, Inn K-S. 83.  et al. 2010. Negative role of RIG-I serine 8 phosphorylation in the regulation of interferon-β production. J. Biol. Chem. 285:20252–61 [Google Scholar]
  84. Wies E, Wang MK, Maharaj NP, Chen K, Zhou S. 84.  et al. 2013. Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling. Immunity 38:437–49 [Google Scholar]
  85. Kim M-J, Hwang S-Y, Imaizumi T, Yoo J-Y. 85.  2008. Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J. Virol. 82:1474–83 [Google Scholar]
  86. Mi Z, Fu J, Xiong Y, Tang H. 86.  2010. SUMOylation of RIG-I positively regulates the type I interferon signaling. Protein Cell 1:275–83 [Google Scholar]
  87. Bozym RA, Delorme-Axford E, Harris K, Morosky S, Ikizler M. 87.  et al. 2012. Focal adhesion kinase is a component of antiviral RIG-I-like receptor signaling. Cell Host Microbe 11:153–66 [Google Scholar]
  88. Hayakawa S, Shiratori S, Yamato H, Kameyama T, Kitatsuji C. 88.  et al. 2011. ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses. Nat. Immunol. 12:37–44 [Google Scholar]
  89. Kok K-H, Lui P-Y, Ng MHJ, Siu K-L, Au SWN, Jin D-Y. 89.  2011. The double-stranded RNA-binding protein PACT functions as a cellular activator of RIG-I to facilitate innate antiviral response. Cell Host Microbe 9:299–309 [Google Scholar]
  90. Chen H, Li Y, Zhang J, Ran Y, Wei J. 90.  et al. 2013. RAVER1 is a coactivator of MDA5-mediated cellular antiviral response. J. Mol. Cell Biol. 5:111–19 [Google Scholar]
  91. Liu HM, Loo Y-M, Horner SM, Zornetzer GA, Katze MG, Gale M Jr. 91.  2012. The mitochondrial targeting chaperone 14-3-3ϵ regulates a RIG-I translocon that mediates membrane association and innate antiviral immunity. Cell Host Microbe 11:528–37 [Google Scholar]
  92. Wang Y, Tong X, Li G, Li J, Deng M, Ye X. 92.  2012. Ankrd17 positively regulates RIG-I-like receptor (RLR)-mediated immune signaling. Eur. J. Immunol. 42:1304–15 [Google Scholar]
  93. Xu L, Xiao N, Liu F, Ren H, Gu J. 93.  2009. Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria. Proc. Natl. Acad. Sci. USA 106:1530–35 [Google Scholar]
  94. Roberts WK, Hovanessian ARA, Brown RE, Clemens MJ, Kerr IM. 94.  1976. Interferon-mediated protein kinase and low-molecular-weight inhibitor of protein synthesis. Nature 264:477–80 [Google Scholar]
  95. Minks MA, West DK, Benvin S, Baglioni C. 95.  1979. Structural requirements of double-stranded RNA for the activation of 2′,5′-oligo(A) polymerase and protein kinase of interferon-treated HeLa cells. J. Biol. Chem. 254:10180–83 [Google Scholar]
  96. Silverman RH. 96.  2007. Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J. Virol. 81:12720–29 [Google Scholar]
  97. Williams BRG. 97.  2001. Signal integration via PKR. Sci. STKE 2001:re2 [Google Scholar]
  98. Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK. 98.  et al. 2000. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity 13:129–41 [Google Scholar]
  99. Yang YL, Reis LF, Pavlovic J, Aguzzi A, Schafer R. 99.  et al. 1995. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 14:6095–106 [Google Scholar]
  100. Stetson DB, Medzhitov R. 100.  2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24:93–103 [Google Scholar]
  101. Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y. 101.  et al. 2006. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7:40–48 [Google Scholar]
  102. Cheng G, Zhong J, Chung J, Chisari FV. 102.  2007. Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells. Proc. Natl. Acad. Sci. USA 104:9035–40 [Google Scholar]
  103. Choi MK, Wang Z, Ban T, Yanai H, Lu Y. 103.  et al. 2009. A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA. Proc. Natl. Acad. Sci. USA 106:4217870–75 [Google Scholar]
  104. Chiu Y-H, MacMillan JB, Chen ZJ. 104.  2009. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576–91 [Google Scholar]
  105. Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V. 105.  2009. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat. Immunol. 10:1065–72 [Google Scholar]
  106. Ishikawa H, Barber GN. 106.  2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–78 [Google Scholar]
  107. Zhong B, Yang Y, Li S, Wang Y-Y, Li Y. 107.  et al. 2008. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–50 [Google Scholar]
  108. Sun W, Li Y, Chen L, Chen H, You F. 108.  et al. 2009. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc. Natl. Acad. Sci. USA 106:8653–58 [Google Scholar]
  109. Ouyang S, Song X, Wang Y, Ru H, Shaw N. 109.  et al. 2012. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. Immunity 36:1073–86 [Google Scholar]
  110. Yin Q, Tian Y, Kabaleeswaran V, Jiang X, Tu D. 110.  et al. 2012. Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol. Cell 46:735–45 [Google Scholar]
  111. Ishikawa H, Ma Z, Barber GN. 111.  2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–92 [Google Scholar]
  112. Sauer J-D, Sotelo-Troha K, von Moltke J, Monroe KM, Rae CS. 112.  et al. 2011. The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 79:688–94 [Google Scholar]
  113. Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T. 113.  et al. 2009. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl. Acad. Sci. USA 106:20842–46 [Google Scholar]
  114. Tanaka Y, Chen ZJ. 114.  2012. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal. 5:ra20 [Google Scholar]
  115. Burdette DL, Vance RE. 115.  2013. STING and the innate immune response to nucleic acids in the cytosol. Nat. Immunol. 14:19–26 [Google Scholar]
  116. Chen H, Sun H, You F, Sun W, Zhou X. 116.  et al. 2011. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 147:436–46 [Google Scholar]
  117. Tamayo R, Pratt JT, Camilli A. 117.  2007. Roles of cyclic diguanylate in the regulation of bacterial pathogenesis. Annu. Rev. Microbiol. 61:131–48 [Google Scholar]
  118. Romling U. 118.  2008. Great times for small molecules: c-di-AMP, a second messenger candidate in Bacteria and Archaea. Sci. Signal. 1:pe39 [Google Scholar]
  119. Davies BW, Bogard RW, Young TS, Mekalanos JJ. 119.  2012. Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 149:358–70 [Google Scholar]
  120. McWhirter SM, Barbalat R, Monroe KM, Fontana MF, Hyodo M. 120.  et al. 2009. A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. J. Exp. Med. 206:1899–911 [Google Scholar]
  121. Woodward JJ, Iavarone AT, Portnoy DA. 121.  2010. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 328:1703–5 [Google Scholar]
  122. Jin L, Hill KK, Filak H, Mogan J, Knowles H. 122.  et al. 2011. MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP. J. Immunol. 187:2595–601 [Google Scholar]
  123. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B. 123.  et al. 2011. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478:515–18 [Google Scholar]
  124. Huang Y-H, Liu X-Y, Du X-X, Jiang Z-F, Su X-D. 124.  2012. The structural basis for the sensing and binding of cyclic di-GMP by STING. Nat. Struct. Mol. Biol. 19:728–30 [Google Scholar]
  125. Shang G, Zhu D, Li N, Zhang J, Zhu C. 125.  et al. 2012. Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP. Nat. Struct. Mol. Biol. 19:725–27 [Google Scholar]
  126. Shu C, Yi G, Watts T, Kao CC, Li P. 126.  2012. Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system. Nat. Struct. Mol. Biol. 19:722–24 [Google Scholar]
  127. Zhang X, Shi H, Wu J, Zhang X, Sun L. 127.  et al. 2013. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51:226–35 [Google Scholar]
  128. Sun L, Wu J, Du F, Chen X, Chen ZJ. 128.  2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–91 [Google Scholar]
  129. Wu J, Sun L, Chen X, Du F, Shi H. 129.  et al. 2013. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–30 [Google Scholar]
  130. Xiao TS, Fitzgerald KA. 130.  2013. The cGAS-STING Pathway for DNA sensing. Mol. Cell 51:135–39 [Google Scholar]
  131. Gao D, Wu J, Wu Y-T, Du F, Aroh C. 131.  et al. 2013. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–6 [Google Scholar]
  132. Li X-D, Wu J, Gao D, Wang H, Sun L, Chen ZJ. 132.  2013. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341:1390–94 [Google Scholar]
  133. Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B. 133.  et al. 2014. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature In press. doi: 10.1038/nature12862
  134. Lahaye X, Satoh T, Gentili M, Cerboni S, Conrad C. 134.  et al. 2013. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells. Immunity 39:1132–42 [Google Scholar]
  135. Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C. 135.  et al. 2013. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503:402–5 [Google Scholar]
  136. Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL. 136.  et al. 2013. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153:1094–107 [Google Scholar]
  137. Kranzusch PJ, Lee AS-Y, Berger JM, Doudna JA. 137.  2013. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep. 3:1362–68 [Google Scholar]
  138. Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M. 138.  et al. 2013. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498:332–37 [Google Scholar]
  139. Diner EJ, Burdette DL, Wilson SC, Monroe KM, Kellenberger CA. 139.  et al. 2013. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 3:1355–61 [Google Scholar]
  140. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G. 140.  et al. 2013. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498:380–84 [Google Scholar]
  141. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T. 141.  et al. 2013. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503:530–34 [Google Scholar]
  142. Konno H, Konno K, Barber GN. 142.  2013. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155:688–98 [Google Scholar]
  143. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA. 143.  et al. 2011. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–61 [Google Scholar]
  144. Alers S, Löffler AS, Wesselborg S, Stork B. 144.  2012. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 32:12–11 [Google Scholar]
  145. Gao P, Ascano M, Zillinger T, Wang W, Dai P. 145.  et al. 2013. Structure-function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell 154:748–62 [Google Scholar]
  146. Paludan SR, Bowie AG. 146.  2013. Immune sensing of DNA. Immunity 38:870–80 [Google Scholar]
  147. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H. 147.  et al. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448:501–5 [Google Scholar]
  148. Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H. 148.  et al. 2008. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451:725–29 [Google Scholar]
  149. Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB. 149.  et al. 2010. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 11:997–1004 [Google Scholar]
  150. Orzalli MH, DeLuca NA, Knipe DM. 150.  2012. Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. Proc. Natl. Acad. Sci. USA 109:E3008–17 [Google Scholar]
  151. Kerur N, Veettil Mohanan V, Sharma-Walia N, Bottero V, Sadagopan S. 151.  et al. 2011. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi sarcoma-associated herpesvirus infection. Cell Host Microbe 9:363–75 [Google Scholar]
  152. Brunette RL, Young JM, Whitley DG, Brodsky IE, Malik HS, Stetson DB. 152.  2012. Extensive evolutionary and functional diversity among mammalian AIM2-like receptors. J. Exp. Med. 209:1969–83 [Google Scholar]
  153. Abe T, Harashima A, Xia T, Konno H, Konno K. 153.  et al. 2013. STING recognition of cytoplasmic DNA instigates cellular defense. Mol. Cell 50:5–15 [Google Scholar]
  154. Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu Y-J. 154.  2011. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat. Immunol. 12:959–65 [Google Scholar]
  155. Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y. 155.  et al. 2012. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat. Immunol. 13:1155–61 [Google Scholar]
  156. Zhang Z, Bao M, Lu N, Weng L, Yuan B, Liu Y-J. 156.  2013. The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA. Nat. Immunol. 14:172–78 [Google Scholar]
  157. Lam E, Stein S, Falck-Pedersen E. 157.  2014. Adenovirus detection by the GAS/STING/TBK1 DNA sensing cascade. J. Virol. 88:974–81 [Google Scholar]
  158. Stein SC, Lam E, Falck-Pedersen E. 158.  2012. Cell-specific regulation of nucleic acid sensor cascades: a controlling interest in the antiviral response. J. Virol. 86:13303–12 [Google Scholar]
  159. Ferguson BJ, Mansur DS, Peters NE, Ren H, Smith GL. 159.  2012. DNA-PK is a DNA sensor for IRF-3-dependent innate immunity. eLife 1:e00047 [Google Scholar]
  160. Zhang X, Brann TW, Zhou M, Yang J, Oguariri RM. 160.  et al. 2011. Cutting edge: Ku70 is a novel cytosolic DNA sensor that induces type III rather than type I IFN. J. Immunol. 186:4541–5 [Google Scholar]
  161. Kondo T, Kobayashi J, Saitoh T, Maruyama K, Ishii KJ. 161.  et al. 2013. DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking. Proc. Natl. Acad. Sci. USA 110:2969–74 [Google Scholar]
  162. Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA. 162.  et al. 2008. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452:103–7 [Google Scholar]
  163. Fernandes-Alnemri T, Yu J-W, Datta P, Wu J, Alnemri ES. 163.  2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509–13 [Google Scholar]
  164. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G. 164.  et al. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514–18 [Google Scholar]
  165. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G. 165.  et al. 2009. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol. 10:266–72 [Google Scholar]
  166. Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM. 166.  et al. 2009. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323:1057–60 [Google Scholar]
  167. Fernandes-Alnemri T, Yu J-W, Juliana C, Solorzano L, Kang S. 167.  et al. 2010. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat. Immunol. 11:385–93 [Google Scholar]
  168. Rathinam VAK, Jiang Z, Waggoner SN, Sharma S, Cole LE. 168.  et al. 2010. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11:395–402 [Google Scholar]
  169. Jones JW, Kayagaki N, Broz P, Henry T, Newton K. 169.  et al. 2010. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc. Natl. Acad. Sci. USA 107:9771–76 [Google Scholar]
  170. Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A. 170.  et al. 2006. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat. Genet. 38:917–20 [Google Scholar]
  171. Morita M, Stamp G, Robins P, Dulic A, Rosewell I. 171.  et al. 2004. Gene-targeted mice lacking the Trex1 (DNase III) 3′→5′ DNA exonuclease develop inflammatory myocarditis. Mol. Cell. Biol. 24:6719–27 [Google Scholar]
  172. Stetson DB, Ko JS, Heidmann T, Medzhitov R. 172.  2008. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–98 [Google Scholar]
  173. Yang Y-G, Lindahl T, Barnes DE. 173.  2007. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–86 [Google Scholar]
  174. Gall A, Treuting P, Elkon KB, Loo Y-M, Gale M Jr. 174.  et al. 2012. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120–31 [Google Scholar]
  175. Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J. 175.  2010. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11:1005–13 [Google Scholar]
  176. Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S. 176.  2005. Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6:49–56 [Google Scholar]
  177. Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y. 177.  et al. 2006. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443:998–1002 [Google Scholar]
  178. Okabe Y, Kawane K, Akira S, Taniguchi T, Nagata S. 178.  2005. Toll-like receptor–independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. 202:1333–39 [Google Scholar]
  179. Ahn J, Gutman D, Saijo S, Barber GN. 179.  2012. STING manifests self DNA-dependent inflammatory disease. Proc. Natl. Acad. Sci. USA 109:19386–91 [Google Scholar]
  180. Li X, Shu C, Yi G, Chaton CT, Shelton CL. 180.  et al. 2013. Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39:61019–31 [Google Scholar]
  181. Zhang X, Wu J, Du F, Xu H, Sun L. 181.  et al. 2014. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. In press. http://dx.doi.org/10.1016/j.celrep.2014.01.003
/content/journals/10.1146/annurev-immunol-032713-120156
Loading
/content/journals/10.1146/annurev-immunol-032713-120156
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error