Discriminating self from non-self in nucleic acid sensing

Nature Reviews Immunology

Volumn 16, Issue 9, 2016, Pages 566-580

  Schlee, Martin ^a   Hartmann, Gunther ^a  

^a UNIVERSITY HOSPITAL BONN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

DEOXYRIBONUCLEASE; INTERFERON; NUCLEIC ACID; PATHOGEN ASSOCIATED MOLECULAR PATTERN;

ANTIVIRAL ACTIVITY; AUTOINFLAMMATORY DISEASE; DNA MODIFICATION; GENE EXPRESSION; HUMAN; INNATE IMMUNITY; MOLECULAR RECOGNITION; NONHUMAN; PRIORITY JOURNAL; RECEPTOR UPREGULATION; REVIEW; RNA SEQUENCE; VERTEBRATE; VIRUS DETECTION; VIRUS IMMUNITY; ANIMAL; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY;

ANIMALS; HUMANS; IMMUNITY, INNATE; NUCLEIC ACIDS; SELF TOLERANCE;

EID: 84980385738     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri.2016.78     Document Type: Review

References (167)

1. Isaacs, A., Cox, R. A. & Rotem, Z. Foreign nucleic acids as the stimulus to make interferon. Lancet 2, 113-116 (1963).
2. Junt, T. & Barchet, W. Translating nucleic acid-sensing pathways into therapies. Nat. Rev. Immunol. 15, 529-544 (2015).
3. Ablasser, A., Hertrich, C., Wassermann, R. & Hornung, V. Nucleic acid driven sterile inflammation. Clin. Immunol. 147, 207-215 (2013).
4. Wu, J. & Chen, Z. J. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32, 461-488 (2014).
5. Kawasaki, T., Kawai, T. & Akira, S. Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol. Rev. 243, 61-73 (2011).
6. Rathinam, V. A. & Fitzgerald, K. A. Cytosolic surveillance and antiviral immunity. Curr. Opin. Virol. 1, 455-462 (2012).
7. Desmet, C. J. & Ishii, K. J. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat. Rev. Immunol. 12, 479-491 (2012).
8. Yoneyama, M. & Fujita, T. Recognition of viral nucleic acids in innate immunity. Rev. Med. Virol. 20, 4-22 (2010).
9. Rehwinkel, J. & Reis e Sousa, C. Targeting the viral Achilles' heel: recognition of 5'-triphosphate RNA in innate anti-viral defence. Curr. Opin. Microbiol. 16, 485-492 (2013).
10. van den Boorn, J. G. & Hartmann, G. Turning tumors into vaccines: co-opting the innate immune system. Immunity 39, 27-37 (2013).
11. Svoboda, P. Renaissance of mammalian endogenous RNAi. FEBS Lett. 588, 2550-2556 (2014).
12. Seo, G. J. et al. Reciprocal inhibition between intracellular antiviral signaling and the RNAi machinery in mammalian cells. Cell Host Microbe 14, 435-445 (2013).
13. Sato, S. et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 42, 123-132 (2015).
14. Weber, M. et al. Influenza virus adaptation PB2-627K modulates nucleocapsid inhibition by the pathogen sensor RIG-I. Cell Host Microbe 17, 309-319 (2015).
15. McAllister, C. S., Taghavi, N. & Samuel, C. E. Protein kinase PKR amplification of interferon β induction occurs through initiation factor eIF-2α-mediated translational control. J. Biol. Chem. 287, 36384-36392 (2012).
16. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732-738 (2001).
17. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529-1531 (2004).
18. Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526-1529 (2004).
19. Hornung, V. et al. Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med. 11, 263-270 (2005).
20. Matsumoto, M. et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J. Immunol. 171, 3154-3162 (2003).
21. Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730-737 (2004).
22. Ahmad, S. & Hur, S. Helicases in antiviral immunity: dual properties as sensors and effectors. Trends Biochem. Sci. 40, 576-585 (2015).
23. Schlee, M. Master sensors of pathogenic RNA - RIG-I like receptors. Immunobiology 218, 1322-1335 (2013).
24. El Maadidi, S. et al. A novel mitochondrial MAVS/ caspase-8 platform links RNA virus-induced innate antiviral signaling to Bax/Bak-independent apoptosis. J. Immunol. 192, 1171-1183 (2014).
25. Besch, R. et al. Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J. Clin. Invest. 119, 2399-2411 (2009).
26. Kumar, S. et al. IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type I interferons-dependent and -independent anticancer activity. Cell Death Dis. 6, e1758 (2015).
27. Glas, M. et al. Targeting the cytosolic innate immune receptors RIG-I and MDA5 effectively counteracts cancer cell heterogeneity in glioblastoma. Stem Cells 31, 1064-1074 (2013).
28. Chattopadhyay, S. et al. Viral apoptosis is induced by IRF-3-mediated activation of Bax. EMBO J. 29, 1762-1773 (2010).
29. Park, S. et al. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J. Immunol. 191, 4358-4366 (2013).
30. Subramanian, N., Natarajan, K., Clatworthy, M. R., Wang, Z. & Germain, R. N. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153, 348-361 (2013).
31. Franchi, L. et al. Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J. Immunol. 193, 4214-4222 (2014).
32. Poeck, H. et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1β production. Nat. Immunol. 11, 63-69 (2010).
33. Pothlichet, J. et al. Type I IFN triggers RIG-I/TLR3/ NLRP3-dependent inflammasome activation in influenza A virus infected cells. PLoS Pathog. 9, e1003256 (2013).
34. Levin, 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 75, 1121-1125 (1978).
35. Daffis, S. et al. 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature 468, 452-456 (2010).
36. Pichlmair, A. et al. IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA. Nat. Immunol. 12, 624-630 (2011).
37. Abbas, Y. M., Pichlmair, A., Gorna, M. W., Superti-Furga, G. & Nagar, B. Structural basis for viral 5'-PPP-RNA recognition by human IFIT proteins. Nature 494, 60-64 (2013).
38. Habjan, M. et al. Sequestration by IFIT1 impairs translation of 2'O-unmethylated capped RNA. PLoS Pathog. 9, e1003663 (2013).
39. Kumar, P. et al. Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5'-terminal regions of cap0-, cap1- and 5'ppp- mRNAs. Nucleic Acids Res. 42, 3228-3245 (2014).
40. Zilberstein, 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 75, 4734-4738 (1978).
41. Hovanessian, A. G., Brown, R. E. & Kerr, I. M. Synthesis of low molecular weight inhibitor of protein synthesis with enzyme from interferon-treated cells. Nature 268, 537-540 (1977).
42. Zhou, A., Hassel, B. A. & Silverman, R. H. Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell 72, 753-765 (1993).
43. George, C. X., John, L. & Samuel, C. E. An RNA editor, adenosine deaminase acting on double-stranded RNA (ADAR1). J. Interferon Cytokine Res. 34, 437-446 (2014).
44. Gelinas, J. F., Clerzius, G., Shaw, E. & Gatignol, A. Enhancement of replication of RNA viruses by ADAR1 via RNA editing and inhibition of RNA-activated protein kinase. J. Virol. 85, 8460-8466 (2011).
45. Weber, F., Wagner, V., Rasmussen, S. B., Hartmann, R. & Paludan, S. R. Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J. Virol. 80, 5059-5064 (2006).
46. Gitlin, L. et al. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl Acad. Sci. USA 103, 8459-8464 (2006).
47. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101-105 (2006).
48. Kato, H. et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 205, 1601-1610 (2008).
49. Goubau, D. et al. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates. Nature 514, 372-375 (2014).
50. Leonard, J. N. et al. The TLR3 signaling complex forms by cooperative receptor dimerization. Proc. Natl Acad. Sci. USA 105, 258-263 (2008).
51. Kleinman, M. E. et al. Short-interfering RNAs induce retinal degeneration via TLR3 and IRF3. Mol. Ther. 20, 101-108 (2012).
52. Weber, C. et al. Toll-like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR-mediated effects). Immunology 136, 64-77 (2012).
53. Tatematsu, M., Nishikawa, F., Seya, T. & Matsumoto, M. Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA. Nat. Commun. 4, 1833 (2013).
54. Wu, B. et al. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152, 276-289 (2013).
55. Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115-1120 (2015).
56. Pestal, K. et al. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity 43, 933-944 (2015).
57. Luthra, P., Sun, D., Silverman, R. H. & He, B. Activation of IFN-β; expression by a viral mRNA through RNase L and MDA5. Proc. Natl Acad. Sci. USA 108, 2118-2123 (2011).
58. Runge, S. et al. In vivo ligands of MDA5 and RIG-I in measles virus-infected cells. PLoS Pathog. 10, e1004081 (2014).
59. Childs, K. et al. MDA-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology 359, 190-200 (2007).
60. Benitez, A. A. et al. In vivo RNAi screening identifies MDA5 as a significant contributor to the cellular defense against influenza A virus. Cell Rep. 11, 1714-1726 (2015).
61. Binder, M. et al. Molecular mechanism of signal perception and integration by the innate immune sensor retinoic acid-inducible gene-I (RIG-I). J. Biol. Chem. 286, 27278-27287 (2011).
62. Minks, M. A., West, D. K., Benvin, S. & Baglioni, C. 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, 10180-10183 (1979).
63. Manche, L., Green, S. R., Schmedt, C. & Mathews, M. B. Interactions between double-stranded RNA regulators and the protein kinase DAI. Mol. Cell. Biol. 12, 5238-5248 (1992).
64. Judge, A. D. et al. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat. Biotechnol. 23, 457-462 (2005).
65. Ablasser, A. et al. Selection of molecular structure and delivery of RNA oligonucleotides to activate TLR7 versus TLR8 and to induce high amounts of IL-12p70 in primary human monocytes. J. Immunol. 182, 6824-6833 (2009).
66. Tanji, H. et al. Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat. Struct. Mol. Biol. 22, 109-115 (2015).
67. Shibata, T. et al. Guanosine and its modified derivatives are endogenous ligands for TLR7. Int. Immunol. 28, 211-222 (2016).
68. Saito, T., Owen, D. M., Jiang, F., Marcotrigiano, J. & Gale, M. Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454, 523-527 (2008).
69. Atkinson, N. J., Witteveldt, J., Evans, D. J. & Simmonds, P. The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication. Nucleic Acids Res. 42, 4527-4545 (2014).
70. Tulloch, F., Atkinson, N. J., Evans, D. J., Ryan, M. D. & Simmonds, P. RNA virus attenuation by codon pair deoptimisation is an artefact of increases in CpG/UpA dinucleotide frequencies. eLife 3, e04531 (2014).
71. Marques, J. T. et al. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat. Biotechnol. 24, 559-565 (2006).
72. Hornung, V. et al. 5'-Triphosphate RNA is the ligand for RIG-I. Science 314, 994-997 (2006).
73. Schlee, M. et al. Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 31, 25-34 (2009).
74. Vela, A., Fedorova, O., Ding, S. C. & Pyle, A. M. The thermodynamic basis for viral RNA detection by the RIG-I innate immune sensor. J. Biol. Chem. 287, 42564-42573 (2012).
75. Marq, J. B., Kolakofsky, D. & Garcin, D. Unpaired 5' ppp-nucleotides, as found in arenavirus double-stranded RNA panhandles, are not recognized by RIG-I. J. Biol. Chem. 285, 18208-18216 (2010).
76. Wang, Y. et al. Structural and functional insights into 5'-ppp RNA pattern recognition by the innate immune receptor RIG-I. Nat. Struct. Mol. Biol. 17, 781-787 (2010).
77. Civril, F. et al. The RIG-I ATPase domain structure reveals insights into ATP-dependent antiviral signalling. EMBO Rep. 12, 1127-1134 (2011).
78. Jiang, F. et al. Structural basis of RNA recognition and activation by innate immune receptor RIG-I. Nature 479, 423-427 (2011).
79. Luo, D. et al. Structural insights into RNA recognition by RIG-I. Cell 147, 409-422 (2011).
80. Kowalinski, E. et al. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell 147, 423-435 (2011).
81. Kohlway, A., Luo, D., Rawling, D. C., Ding, S. C. & Pyle, A. M. Defining the functional determinants for RNA surveillance by RIG-I. EMBO Rep. 14, 772-779 (2013).
82. Monroe, K. M., McWhirter, S. M. & Vance, R. E. Identification of host cytosolic sensors and bacterial factors regulating the type I interferon response to Legionella pneumophila. PLoS Pathog. 5, e1000665 (2009).
83. Abdullah, Z. et al. RIG-I detects infection with live Listeria by sensing secreted bacterial nucleic acids. EMBO J. 31, 4153-4164 (2012).
84. Hagmann, C. A. et al. RIG-I detects triphosphorylated RNA of Listeria monocytogenes during infection in non-immune cells. PLoS ONE 8, e62872 (2013).
85. Strahle, L., Garcin, D. & Kolakofsky, D. Sendai virus defective-interfering genomes and the activation of interferon-beta. Virology 351, 101-111 (2006).
86. Nallagatla, S. R. et al. 5'-Triphosphate-dependent activation of PKR by RNAs with short stem-loops. Science 318, 1455-1458 (2007).
87. Eigenbrod, T. & Dalpke, A. H. Bacterial RNA: an underestimated stimulus for innate immune responses. J. Immunol. 195, 411-418 (2015).
88. Kariko, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165-175 (2005).
89. Eberle, F. et al. Modifications in small interfering RNA that separate immunostimulation from RNA interference. J. Immunol. 180, 3229-3237 (2008).
90. Schuberth-Wagner, C. et al. A conserved histidine in the RNA sensor RIG-I controls immune tolerance to N1-2'O-methylated self RNA. Immunity 43, 41-51 (2015).
91. Devarkar, S. C. et al. Structural basis for m7G recognition and 2'-O-methyl discrimination in capped RNAs by the innate immune receptor RIG-I. Proc. Natl Acad. Sci. USA 113, 596-601 (2016).
92. Zust, R. et al. Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat. Immunol. 12, 137-143 (2011).
93. Hyde, J. L. & Diamond, M. S. Innate immune restriction and antagonism of viral RNA lacking 2-O methylation. Virology 479-480, 66-74 (2015).
94. Hyde, J. L. et al. A viral RNA structural element alters host recognition of nonself RNA. Science 343, 783-787 (2014).
95. Habjan, M. et al. Processing of genome 5' termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction. PLoS ONE 3, e2032 (2008).
96. Anchisi, S., Guerra, J., Mottet-Osman, G. & Garcin, D. Mismatches in the influenza A virus RNA panhandle prevent retinoic acid-inducible gene I (RIG-I) sensing by impairing RNA/RIG-I complex formation. J. Virol. 90, 586-590 (2015).
97. Yu, P. et al. Nucleic acid-sensing Toll-like receptors are essential for the control of endogenous retrovirus viremia and ERV-induced tumors. Immunity 37, 867-879 (2012).
98. Malathi, K., Dong, B., Gale, M. Jr & Silverman, R. H. Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448, 816-819 (2007).
99. Cho, J. A. et al. The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13, 558-569 (2013).
100. Eckard, S. C. et al. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat. Immunol. 15, 839-845 (2014).
101. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740-745 (2000).
102. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514-518 (2009).
103. Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509-513 (2009).
104. Burckstummer, T. et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat. Immunol. 10, 266-272 (2009).
105. Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11, 395-402 (2010).
106. Kerur, N. et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi sarcoma-associated herpesvirus infection. Cell Host Microbe 9, 363-375 (2011).
107. Monroe, K. M. et al. IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV-. Science 343, 428-432 (2014).
108. Jakobsen, M. R. et al. From the cover: IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication. Proc. Natl Acad. Sci. USA 110, E4571-E4580 (2013).
109. Roth, S. et al. Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production. Nat. Immunol. 15, 538-545 (2014).
110. Ishii, K. J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7, 40-48 (2006).
111. Ablasser, A. et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat. Immunol. 10, 1065-1072 (2009).
112. Chiu, Y. H., Macmillan, J. B. & Chen, Z. J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576-591 (2009).
113. Stetson, D. B. & Medzhitov, R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93-103 (2006).
114. Paludan, S. R. Activation and regulation of DNA-driven immune responses. Microbiol. Mol. Biol. Rev. 79, 225-241 (2015).
115. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788-792 (2009).
116. Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538-550 (2008).
117. Sauer, J. D. et al. 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, 688-694 (2011).
118. Burdette, D. L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515-518 (2011).
119. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786-791 (2013).
120. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826-830 (2012).
121. Gao, P. et al. Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153, 1094-1107 (2013).
122. Ablasser, A. et al. cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380-384 (2013).
123. Civril, F. et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498, 332-337 (2013).
124. Kato, K. et al. Structural and functional analyses of DNA-sensing and immune activation by human cGAS. PLoS ONE 8, e76983 (2013).
125. Kranzusch, P. J., Lee, A. S., Berger, J. M. & Doudna, J. A. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep. 3, 1362-1368 (2013).
126. Gao, D. et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV- and other retroviruses. Science 341, 903-906 (2013).
127. Zhang, X. et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. 6, 421-430 (2014).
128. Li, X. et al. Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39, 1019-1031 (2013).
129. Li, X. D. et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390-1394 (2013).
130. Lam, E., Stein, S. & Falck-Pedersen, E. Adenovirus detection by the cGAS/STING/TBK1 DNA sensing cascade. J. Virol. 88, 974-981 (2014).
131. Lahaye, X. et al. 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, 1132-1142 (2013).
132. Rasaiyaah, J. et al. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503, 402-405 (2013).
133. Herzner, A. M. et al. Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nat. Immunol. 16, 1025-1033 (2015).
134. Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 11, 997-1004 (2010).
135. Jakobsen, M. R. & Paludan, S. R. IFI16: at the interphase between innate DNA sensing and genome regulation. Cytokine Growth Factor Rev. 25, 649-655 (2014).
136. Dutta, D. et al. BRCA1 regulates IFI16 mediated nuclear innate sensing of herpes viral DNA and subsequent induction of the innate inflammasome and interferon-β responses. PLoS Pathog. 11, e1005030 (2015).
137. Ferguson, B. J., Mansur, D. S., Peters, N. E., Ren, H. & Smith, G. L. DNA-PK is a DNA sensor for IRF-3-dependent innate immunity. eLife 1, e00047 (2012).
138. Yoh, S. M. et al. PQBP1 Is a proximal sensor of the cGAS-dependent innate response to HIV-1. Cell 161, 1293-1305 (2015).
139. Jin, T. et al. Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36, 561-571 (2012).
140. Martin-Gayo, E. et al. Potent cell-intrinsic immune responses in dendritic cells facilitate HIV-1-specific T cell immunity in HIV-1 elite controllers. PLoS Pathog. 11, e1004930 (2015).
141. Krieg, A. M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546-549 (1995).
142. Hartmann, G. & Krieg, A. M. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J. Immunol. 164, 944-953 (2000).
143. Coch, C. et al. Higher activation of TLR9 in plasmacytoid dendritic cells by microbial DNA compared with self-DNA based on CpG-specific recognition of phosphodiester DNA. J. Leukoc. Biol. 86, 663-670 (2009).
144. Rigby, R. E. et al. RNA:DNA hybrids are a novel molecular pattern sensed by TLR9. EMBO J. 33, 542-558 (2014).
145. Mankan, A. K. et al. Cytosolic RNA:DNA hybrids activate the cGAS-STING axis. EMBO J. 33, 2937-2946 (2014).
146. Gehrke, N. et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482-495 (2013).
147. Napirei, M. et al. Features of systemic lupus erythematosus in DNase1-deficient mice. Nat. Genet. 25, 177-181 (2000).
148. Lan, Y. Y., Londono, D., Bouley, R., Rooney, M. S. & Hacohen, N. DNase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep. 9, 180-192 (2014).
149. Yoshida, H., Okabe, Y., Kawane, K., Fukuyama, H. & Nagata, S. Lethal anemia caused by interferon-β produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6, 49-56 (2005).
150. Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998-1002 (2006).
151. Baum, R. et al. Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice. J. Immunol. 194, 873-877 (2015).
152. Jakobs, C., Perner, S. & Hornung, V. AIM2 drives joint inflammation in a self-DNA triggered model of chronic polyarthritis. PLoS ONE 10, e0131702 (2015).
153. Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587-598 (2008).
154. Gao, D. et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc. Natl Acad. Sci. USA 112, E5699-E5705 (2015).
155. Ablasser, A. et al. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192, 5993-5997 (2014).
156. Gray, E. E., Treuting, P. M., Woodward, J. J. & Stetson, D. B. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutieres syndrome. J. Immunol. 195, 1939-1943 (2015).
157. Chan, M. P. et al. DNase II-dependent DNA digestion is required for DNA sensing by TLR9. Nat. Commun. 6, 5853 (2015).
158. Kono, H., Kimura, Y. & Latz, E. Inflammasome activation in response to dead cells and their metabolites. Curr. Opin. Immunol. 30, 91-98 (2014).
159. Crow, Y. J. et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am. J. Med. Genet. A 167, 296-312 (2015).
160. Lassig, C. et al. ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA. eLife 4, e10859 (2015).
161. Liu, Y. et al. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371, 507-518 (2014).
162. Shigemoto, T. et al. Identification of loss of function mutations in human genes encoding RIG-I and MDA5: implications for resistance to type I diabetes. J. Biol. Chem. 284, 13348-13354 (2009).
163. Cen, H. et al. Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Autoimmunity 46, 455-462 (2013).
164. Smith, S. & Jefferies, C. Role of DNA/RNA sensors and contribution to autoimmunity. Cytokine Growth Factor Rev. 25, 745-757 (2014).
165. Li, X. D. et al. Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc. Natl Acad. Sci. USA 108, 17390-17395 (2011).
166. Wang, Y. et al. Rig-I-/- mice develop colitis associated with downregulation of Gαi2. Cell Res. 17, 858-868 (2007).
167. Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94-98 (2014).