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Regulation of cGAS- and RLR-mediated immunity to nucleic acids

Abstract

Pathogen-derived nucleic acids are crucial signals for innate immunity. Despite the structural similarity between those and host nucleic acids, mammalian cells have been able to evolve powerful innate immune signaling pathways that originate from the detection of cytosolic nucleic acid species, one of the most prominent being the cGAS–STING pathway for DNA and the RLR–MAVS pathway for RNA, respectively. Recent advances have revealed a plethora of regulatory mechanisms that are crucial for balancing the activity of nucleic acid sensors for the maintenance of overall cellular homeostasis. Elucidation of the various mechanisms that enable cells to maintain control over the activity of cytosolic nucleic acid sensors has provided new insight into the pathology of human diseases and, at the same time, offers a rich and largely unexplored source for new therapeutic targets. This Review addresses the emerging literature on regulation of the sensing of cytosolic DNA and RNA via cGAS and RLRs.

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Fig. 1: Sensing of dsDNA by the cGAS–STING pathway.
Fig. 2: The RLR signal-transduction pathway.
Fig. 3: Regulatory mechanism that acts on DNA-mediated activation of cGAS.

References

  1. 1.

    Barbalat, R., Ewald, S. E., Mouchess, M. L. & Barton, G. M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).

    CAS  PubMed  Google Scholar 

  2. 2.

    Paludan, S. R. & Bowie, A. G. Immune sensing of DNA. Immunity 38, 870–880 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Ablasser, A. & Chen, Z. J. cGAS in action: expanding roles in immunity and inflammation. Science 363, eaat8657 (2019).

    CAS  PubMed  Google Scholar 

  4. 4.

    Hur, S. Double-stranded RNA sensors and modulators in innate immunity. Annu. Rev. Immunol. 37, 349–375 (2019).

    CAS  PubMed  Google Scholar 

  5. 5.

    Roers, A., Hiller, B. & Hornung, V. Recognition of endogenous nucleic acids by the innate immune system. Immunity 44, 739–754 (2016).

    CAS  PubMed  Google Scholar 

  6. 6.

    Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Ishizuka, J. J. et al. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565, 43–48 (2019).

    CAS  Google Scholar 

  8. 8.

    Glück, S. & Ablasser, A. Innate immunosensing of DNA in cellular senescence. Curr. Opin. Immunol. 56, 31–36 (2019).

    PubMed  Google Scholar 

  9. 9.

    Crowl, J. T., Gray, E. E., Pestal, K., Volkman, H. E. & Stetson, D. B. Intracellular nucleic acid detection in autoimmunity. Annu. Rev. Immunol. 35, 313–336 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    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).

    CAS  PubMed  Google Scholar 

  11. 11.

    Ablasser, A. et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Diner, E. J. et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 3, 1355–1361 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Zhang, X. et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51, 226–235 (2013).

    CAS  PubMed  Google Scholar 

  15. 15.

    Kato, K., Omura, H., Ishitani, R. & Nureki, O. Cyclic GMP-AMP as an endogenous second messenger in innate immune signaling by cytosolic DNA. Annu. Rev. Biochem. 86, 541–566 (2017).

    CAS  PubMed  Google Scholar 

  16. 16.

    Li, X. et al. Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39, 1019–1031 (2013).

    CAS  PubMed  Google Scholar 

  17. 17.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Andreeva, L. et al. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature 549, 394–398 (2017).

    CAS  PubMed  Google Scholar 

  19. 19.

    Hooy, R. M. & Sohn, J. The allosteric activation of cGAS underpins its dynamic signaling landscape. eLife 7, e39984 (2018).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Du, M. & Chen, Z. J. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361, 704–709 (2018).

    CAS  PubMed  Google Scholar 

  21. 21.

    Tao, J. et al. Nonspecific DNA Binding of cGAS N terminus promotes cGAS activation. J. Immunol. 198, 3627–3636 (2017).

    CAS  PubMed  Google Scholar 

  22. 22.

    Xie, W. et al. Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation. Proc. Natl Acad. Sci. USA 116, 11946–11955 (2019).

    CAS  PubMed  Google Scholar 

  23. 23.

    Ablasser, A. et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503, 530–534 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bridgeman, A. et al. Viruses transfer the antiviral second messenger cGAMP between cells. Science 349, 1228–1232 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gentili, M. et al. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349, 1232–1236 (2015).

    CAS  PubMed  Google Scholar 

  26. 26.

    Ritchie, C., Cordova, A. F., Hess, G. T., Bassik, M. C. & Li, L. SLC19A1 is an importer of the immunotransmitter cGAMP. Mol. Cell 75, 372–381.e5 (2019).

    CAS  PubMed  Google Scholar 

  27. 27.

    Carozza, J.A. et al. 2′3′-cGAMP is an immunotransmitter produced by cancer cells and regulated by ENPP1. Preprint at https://doi.org/10.1101/539312 (2019).

  28. 28.

    Ergun, S. L., Fernandez, D., Weiss, T. M. & Li, L. STING polymer structure reveals mechanisms for activation, hyperactivation, and inhibition. Cell 178, 290–301.e10 (2019).

    CAS  PubMed  Google Scholar 

  29. 29.

    Shang, G., Zhang, C., Chen, Z. J., Bai, X. C. & Zhang, X. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Nature 567, 389–393 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Gui, X. et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 567, 262–266 (2019).

    CAS  PubMed  Google Scholar 

  31. 31.

    Dobbs, N. et al. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18, 157–168 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Stempel, M., Chan, B. & Brinkmann, M. M. Coevolution pays off: herpesviruses have the license to escape the DNA sensing pathway. Med. Microbiol. Immunol. 208, 495–512 (2019).

    PubMed  Google Scholar 

  33. 33.

    Zhang, C. et al. Structural basis of STING binding with and phosphorylation by TBK1. Nature 567, 394–398 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Zhao, B. et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature 569, 718–722 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Liu, S. et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 (2015).

    PubMed  Google Scholar 

  36. 36.

    Saitoh, T. et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl Acad. Sci. USA 106, 20842–20846 (2009).

    CAS  PubMed  Google Scholar 

  37. 37.

    Gulen, M. F. et al. Signalling strength determines proapoptotic functions of STING. Nat. Commun. 8, 427 (2017).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Larkin, B. et al. Cutting edge: activation of STING in T cells induces type I IFN responses and cell death. J. Immunol. 199, 397–402 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Fang, R. et al. MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner. PLoS Pathog. 13, e1006720 (2017).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Lei, Y. et al. MAVS-mediated apoptosis and its inhibition by viral proteins. PLoS One 4, e5466 (2009).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Guan, K. et al. MAVS regulates apoptotic cell death by decreasing K48-linked ubiquitination of voltage-dependent anion channel 1. Mol. Cell. Biol. 33, 3137–3149 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Huang, Y. et al. MAVS-MKK7-JNK2 defines a novel apoptotic signaling pathway during viral infection. PLoS Pathog. 10, e1004020 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Yoneyama, M. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175, 2851–2858 (2005).

    CAS  PubMed  Google Scholar 

  44. 44.

    Rothenfusser, S. et al. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J. Immunol. 175, 5260–5268 (2005).

    CAS  PubMed  Google Scholar 

  45. 45.

    Saito, T. et al. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc. Natl Acad. Sci. USA 104, 582–587 (2007).

    CAS  PubMed  Google Scholar 

  46. 46.

    Venkataraman, T. et al. Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. J. Immunol. 178, 6444–6455 (2007).

    CAS  PubMed  Google Scholar 

  47. 47.

    Satoh, T. et al. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc. Natl Acad. Sci. USA 107, 1512–1517 (2010).

    CAS  PubMed  Google Scholar 

  48. 48.

    van der Veen, A. G. et al. The RIG-I-like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells. EMBO J. 37, e97479 (2018).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Bruns, A. M., Leser, G. P., Lamb, R. A. & Horvath, C. M. The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament assembly. Mol. Cell 55, 771–781 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    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).

    CAS  PubMed  Google Scholar 

  51. 51.

    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).

    CAS  PubMed  Google Scholar 

  52. 52.

    Jiang, X. et al. Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates antiviral innate immune response. Immunity 36, 959–973 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Wu, B. et al. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell 152, 276–289 (2013).

    CAS  PubMed  Google Scholar 

  54. 54.

    Peisley, A., Wu, B., Xu, H., Chen, Z. J. & Hur, S. Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I. Nature 509, 110–114 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Peisley, A., Wu, B., Yao, H., Walz, T. & Hur, S. RIG-I forms signaling-competent filaments in an ATP-dependent, ubiquitin-independent manner. Mol. Cell 51, 573–583 (2013).

    CAS  PubMed  Google Scholar 

  56. 56.

    Cadena, C. et al. Ubiquitin-dependent and -independent roles of E3 Ligase RIPLET in innate immunity. Cell 177, 1187–1200.e16 (2019).

    CAS  PubMed  Google Scholar 

  57. 57.

    Wu, B. et al. Molecular imprinting as a signal-activation mechanism of the viral RNA sensor RIG-I. Mol. Cell 55, 511–523 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Hou, F. et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448–461 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Luecke, S. et al. cGAS is activated by DNA in a length-dependent manner. EMBO Rep. 18, 1707–1715 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    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).

    CAS  PubMed  Google Scholar 

  61. 61.

    Steinhagen, F. et al. Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes. Eur. J. Immunol. 48, 605–611 (2018).

    CAS  PubMed  Google Scholar 

  62. 62.

    Lahaye, X. et al. NONO detects the nuclear HIV capsid to promote cGAS-mediated innate immune activation. Cell 175, 488–501.e22 (2018).

    CAS  PubMed  Google Scholar 

  63. 63.

    Zierhut, C. et al. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell 178, 302–315.e23 (2019).

    CAS  PubMed  Google Scholar 

  64. 64.

    Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Crow, Y. J. & Manel, N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–440 (2015).

    CAS  PubMed  Google Scholar 

  66. 66.

    Uggenti, C., Lepelley, A. & Crow, Y. J. Self-awareness: nucleic acid-driven inflammation and the type I interferonopathies. Annu. Rev. Immunol. 37, 247–267 (2019).

    CAS  PubMed  Google Scholar 

  67. 67.

    Crow, Y. J. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).

    CAS  PubMed  Google Scholar 

  68. 68.

    Rice, G. I. et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat. Genet. 41, 829–832 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Crow, Y. J. et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat. Genet. 38, 910–916 (2006).

    CAS  PubMed  Google Scholar 

  70. 70.

    Lindahl, T., Gally, J. A. & Edelman, G. M. Properties of deoxyribonuclease 3 from mammalian tissues. J. Biol. Chem. 244, 5014–5019 (1969).

    CAS  PubMed  Google Scholar 

  71. 71.

    Goldstone, D. C. et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480, 379–382 (2011).

    CAS  PubMed  Google Scholar 

  72. 72.

    Reijns, M. A. et al. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149, 1008–1022 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Gall, A. et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36, 120–131 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Ablasser, A. et al. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192, 5993–5997 (2014).

    CAS  PubMed  Google Scholar 

  75. 75.

    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).

    CAS  PubMed  Google Scholar 

  76. 76.

    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-Goutières syndrome. J. Immunol. 195, 1939–1943 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Mackenzie, K. J. et al. Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J. 35, 831–844 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Maelfait, J., Bridgeman, A., Benlahrech, A., Cursi, C. & Rehwinkel, J. Restriction by SAMHD1 limits cGAS/STING-dependent innate and adaptive immune responses to HIV-1. Cell Rep. 16, 1492–1501 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Pokatayev, V. et al. RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J. Exp. Med. 213, 329–336 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Volkman, H. E. & Stetson, D. B. The enemy within: endogenous retroelements and autoimmune disease. Nat. Immunol. 15, 415–422 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Rice, G. I. et al. Reverse-transcriptase inhibitors in the Aicardi–Goutières syndrome. N. Engl. J. Med. 379, 2275–2277 (2018).

    PubMed  Google Scholar 

  82. 82.

    Yang, Y. G., Lindahl, T. & Barnes, D. E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873–886 (2007).

    CAS  PubMed  Google Scholar 

  83. 83.

    Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Coquel, F. et al. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature 557, 57–61 (2018).

    CAS  PubMed  Google Scholar 

  85. 85.

    Gratia, M. et al. Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS. J. Exp. Med. 216, 1199–1213 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006).

    CAS  PubMed  Google Scholar 

  87. 87.

    Ahn, J., Gutman, D., Saijo, S. & Barber, G. N. STING manifests self DNA-dependent inflammatory disease. Proc. Natl Acad. Sci. USA 109, 19386–19391 (2012).

    CAS  PubMed  Google Scholar 

  88. 88.

    Rodero, M. P. et al. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nat. Commun. 8, 2176 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Lan, Y. Y., Londoño, 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Sisquella, X. et al. Malaria parasite DNA-harbouring vesicles activate cytosolic immune sensors. Nat. Commun. 8, 1985 (2017).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Nandakumar, R. et al. Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling. Nat. Microbiol. 4, 701–713 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Aguirre, S. et al. Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection. Nat. Microbiol. 2, 17037 (2017).

    CAS  PubMed  Google Scholar 

  94. 94.

    Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).

    CAS  PubMed  Google Scholar 

  95. 95.

    McArthur, K. et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, eaao6047 (2018).

    PubMed  Google Scholar 

  96. 96.

    Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Wiens, K. E. & Ernst, J. D. The mechanism for type I interferon induction by Mycobacterium tuberculosis is bacterial strain-dependent. PLoS Pathog. 12, e1005809 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Hatch, E. M., Fischer, A. H., Deerinck, T. J. & Hetzer, M. W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Liu, S. et al. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 561, 551–555 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Ivanov, A. et al. Lysosome-mediated processing of chromatin in senescence. J. Cell Biol. 202, 129–143 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Glück, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Yang, H., Wang, H., Ren, J., Chen, Q. & Chen, Z. J. cGAS is essential for cellular senescence. Proc. Natl Acad. Sci. USA 114, E4612–E4620 (2017).

    CAS  PubMed  Google Scholar 

  106. 106.

    Härtlova, A. et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity 42, 332–343 (2015).

    PubMed  Google Scholar 

  107. 107.

    Wolf, C. et al. RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat. Commun. 7, 11752 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Hornung, V. et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).

    PubMed  Google Scholar 

  109. 109.

    Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006).

    CAS  PubMed  Google Scholar 

  110. 110.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Ahmad, S. et al. Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation. Cell 172, 797–810.e13 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Fitzgerald, M. E., Rawling, D. C., Vela, A. & Pyle, A. M. An evolving arsenal: viral RNA detection by RIG-I-like receptors. Curr. Opin. Microbiol. 20, 76–81 (2014).

    CAS  PubMed  Google Scholar 

  114. 114.

    Sohn, J. & Hur, S. Filament assemblies in foreign nucleic acid sensors. Curr. Opin. Struct. Biol. 37, 134–144 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    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).

    CAS  PubMed  Google Scholar 

  116. 116.

    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).

    CAS  PubMed  Google Scholar 

  117. 117.

    Uzri, D. & Gehrke, L. Nucleotide sequences and modifications that determine RIG-I/RNA binding and signaling activities. J. Virol. 83, 4174–4184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Chen, Y. G. et al. Sensing self and foreign circular RNAs by intron identity. Mol. Cell 67, 228–238.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Chen, Y. G. et al. N6-methyladenosine modification controls circular RNA immunity. Mol. Cell 76, 96–109.e9 (2019).

    CAS  PubMed  Google Scholar 

  120. 120.

    Mu, X., Greenwald, E., Ahmad, S. & Hur, S. An origin of the immunogenicity of in vitro transcribed RNA. Nucleic Acids Res. 46, 5239–5249 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Mannion, N. M. et al. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9, 1482–1494 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Rice, G. I. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243–1248 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Züst, 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).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Dong, H. et al. Flavivirus RNA methylation. J. Gen. Virol. 95, 763–778 (2014).

    CAS  PubMed  Google Scholar 

  127. 127.

    Nabet, B. Y. et al. Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer. Cell 170, 352–366.e13 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Ranoa, D. R. et al. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs. Oncotarget 7, 26496–26515 (2016).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Chiang, J. J. et al. Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity. Nat. Immunol. 19, 53–62 (2018).

    CAS  Google Scholar 

  130. 130.

    Eckard, S. C. et al. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat. Immunol. 15, 839–845 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Dhir, A. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560, 238–242 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Cuellar, T. L. et al. Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia. J. Cell Biol. 216, 3535–3549 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Sheng, W. et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell 174, 549–563.e19 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Hayman, T. J. et al. RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses. Immunol. Cell Biol. 97, 840–852 (2019).

    CAS  PubMed  Google Scholar 

  137. 137.

    Zhou, W. et al. Structure of the Human cGAS-DNA complex reveals enhanced control of immune surveillance. Cell 174, 300–311.e11 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Barnett, K. C. et al. Phosphoinositide interactions position cGAS at the plasma membrane to ensure efficient distinction between self- and viral DNA. Cell 176, 1432–1446.e11 (2019).

    CAS  PubMed  Google Scholar 

  139. 139.

    Gentili, M. et al. The N-terminal domain of cGAS determines preferential association with centromeric DNA and innate immune activation in the nucleus. Cell Rep. 26, 3798 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Volkman, H.E., Cambier, S., Gray, E.E. & Stetson, D.B. cGAS is predominantly a nuclear protein. Preprint at https://doi.org/10.1101/486118 (2019).

  141. 141.

    Jiang, H. et al. Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death. EMBO J. 38, e102718 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Wies, E. et al. Dephosphorylation of the RNA sensors RIG-I and MDA5 by the phosphatase PP1 is essential for innate immune signaling. Immunity 38, 437–449 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Patel, J. R. et al. ATPase-driven oligomerization of RIG-I on RNA allows optimal activation of type-I interferon. EMBO Rep. 14, 780–787 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Devarkar, S. C., Schweibenz, B., Wang, C., Marcotrigiano, J. & Patel, S. S. RIG-I uses an ATPase-powered translocation-throttling mechanism for kinetic proofreading of RNAs and oligomerization. Mol. Cell 72, 355–368.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Peisley, A. et al. Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc. Natl Acad. Sci. USA 108, 21010–21015 (2011).

    CAS  PubMed  Google Scholar 

  147. 147.

    Peisley, A. et al. Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments. Proc. Natl Acad. Sci. USA 109, E3340–E3349 (2012).

    CAS  PubMed  Google Scholar 

  148. 148.

    Wang, W. et al. RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation. Proc. Natl Acad. Sci. USA 113, 9581–9586 (2016).

    CAS  PubMed  Google Scholar 

  149. 149.

    Arimoto, K. et al. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc. Natl Acad. Sci. USA 104, 7500–7505 (2007).

    CAS  PubMed  Google Scholar 

  150. 150.

    Hao, Q. et al. A non-canonical role of the p97 complex in RIG-I antiviral signaling. EMBO J. 34, 2903–2920 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Wang, S. et al. RNF123 has an E3 ligase-independent function in RIG-I-like receptor-mediated antiviral signaling. EMBO Rep. 17, 1155–1168 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Narayan, K. et al. TRIM13 is a negative regulator of MDA5-mediated type I interferon production. J. Virol. 88, 10748–10757 (2014).

    PubMed  PubMed Central  Google Scholar 

  153. 153.

    Zhao, C. et al. The E3 ubiquitin ligase TRIM40 attenuates antiviral immune responses by targeting MDA5 and RIG-I. Cell Rep. 21, 1613–1623 (2017).

    CAS  PubMed  Google Scholar 

  154. 154.

    Zhao, K. et al. Cytoplasmic STAT4 promotes antiviral type I IFN production by blocking CHIP-mediated degradation of RIG-I. J. Immunol. 196, 1209–1217 (2016).

    CAS  PubMed  Google Scholar 

  155. 155.

    Inn, K. S. et al. Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction. Mol. Cell 41, 354–365 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Chen, W. et al. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell 152, 467–478 (2013).

    CAS  PubMed  Google Scholar 

  157. 157.

    Takashima, K., Oshiumi, H., Matsumoto, M. & Seya, T. DNAJB1/HSP40 suppresses melanoma differentiation-associated gene 5-mitochondrial antiviral signaling protein function in conjunction with HSP70. J. Innate Immun. 10, 44–55 (2018).

    CAS  PubMed  Google Scholar 

  158. 158.

    Eaglesham, J. B., Pan, Y., Kupper, T. S. & Kranzusch, P. J. Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling. Nature 566, 259–263 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Li, L. et al. Hydrolysis of 2‘3’-cGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat. Chem. Biol. 10, 1043–1048 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Luteijn, R. D. et al. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature 573, 434–438 (2019).

    CAS  PubMed  Google Scholar 

  161. 161.

    Mukai, K. et al. Activation of STING requires palmitoylation at the Golgi. Nat. Commun. 7, 11932 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).

    CAS  PubMed  Google Scholar 

  163. 163.

    Jeremiah, N. et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Invest. 124, 5516–5520 (2014).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Liu, Y. et al. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371, 507–518 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Srikanth, S. et al. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat. Immunol. 20, 152–162 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Wang, Q. et al. The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity 41, 919–933 (2014).

    CAS  PubMed  Google Scholar 

  167. 167.

    Chen, W. et al. ER adaptor SCAP translocates and recruits IRF3 to perinuclear microsome induced by cytosolic microbial DNAs. PLoS Pathog. 12, e1005462 (2016).

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Luo, W. W. et al. iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING. Nat. Immunol. 17, 1057–1066 (2016).

    CAS  PubMed  Google Scholar 

  169. 169.

    Vece, T. J. et al. Copa syndrome: a novel autosomal dominant immune dysregulatory disease. J. Clin. Immunol. 36, 377–387 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Gonugunta, V. K. et al. Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response. Cell Rep. 21, 3234–3242 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Shen, Y. Y. et al. Adaptive evolution of energy metabolism genes and the origin of flight in bats. Proc. Natl Acad. Sci. USA 107, 8666–8671 (2010).

    CAS  PubMed  Google Scholar 

  172. 172.

    Seluanov, A., Gladyshev, V. N., Vijg, J. & Gorbunova, V. Mechanisms of cancer resistance in long-lived mammals. Nat. Rev. Cancer 18, 433–441 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Xie, J. et al. Dampened STING-dependent interferon activation in bats. Cell Host Microbe 23, 297–301.e4 (2018).

    CAS  PubMed  Google Scholar 

  174. 174.

    Brubaker, S. W., Gauthier, A. E., Mills, E. W., Ingolia, N. T. & Kagan, J. C. A bicistronic MAVS transcript highlights a class of truncated variants in antiviral immunity. Cell 156, 800–811 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Qi, N. et al. Multiple truncated isoforms of MAVS prevent its spontaneous aggregation in antiviral innate immune signalling. Nat. Commun. 8, 15676 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Shi, Y. et al. An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response. Nat. Commun. 6, 7811 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Gu, W. et al. Distinct argonaute-mediated 22G-RNA pathways direct genome surveillance in the C. elegans germline. Mol. Cell 36, 231–244 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    You, F. et al. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nat. Immunol. 10, 1300–1308 (2009).

    CAS  PubMed  Google Scholar 

  179. 179.

    Zhong, B. et al. The E3 ubiquitin ligase RNF5 targets virus-induced signaling adaptor for ubiquitination and degradation. J. Immunol. 184, 6249–6255 (2010).

    CAS  PubMed  Google Scholar 

  180. 180.

    Castanier, C. et al. MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors. BMC Biol. 10, 44 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Pan, Y. et al. Smurf2 negatively modulates RIG-I-dependent antiviral response by targeting VISA/MAVS for ubiquitination and degradation. J. Immunol. 192, 4758–4764 (2014).

    CAS  PubMed  Google Scholar 

  182. 182.

    Du, J. et al. pVHL negatively regulates antiviral signaling by targeting MAVS for proteasomal degradation. J. Immunol. 195, 1782–1790 (2015).

    CAS  PubMed  Google Scholar 

  183. 183.

    Xia, P. et al. IRTKS negatively regulates antiviral immunity through PCBP2 sumoylation-mediated MAVS degradation. Nat. Commun. 6, 8132 (2015).

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    Yoo, Y. S. et al. The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling. Nat. Commun. 6, 7910 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Jin, S. et al. Tetherin suppresses type I interferon signaling by targeting MAVS for NDP52-mediated selective autophagic degradation in human cells. Mol. Cell 68, 308–322.e4 (2017).

    CAS  PubMed  Google Scholar 

  186. 186.

    Qin, Y. et al. NLRX1 mediates MAVS degradation to attenuate the hepatitis C virus-induced innate immune response through PCBP2. J. Virol. 91, e01264–e17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    He, X. et al. RNF34 functions in immunity and selective mitophagy by targeting MAVS for autophagic degradation. EMBO J. 38, e100978 (2019).

    PubMed  PubMed Central  Google Scholar 

  188. 188.

    Vitour, D. et al. Polo-like kinase 1 (PLK1) regulates interferon (IFN) induction by MAVS. J. Biol. Chem. 284, 21797–21809 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Song, T. et al. c-Abl tyrosine kinase interacts with MAVS and regulates innate immune response. FEBS Lett. 584, 33–38 (2010).

    CAS  PubMed  Google Scholar 

  190. 190.

    Xiang, W. et al. PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1. Sci. Adv. 2, e1501889 (2016).

    PubMed  PubMed Central  Google Scholar 

  191. 191.

    Castanier, C., Garcin, D., Vazquez, A. & Arnoult, D. Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. EMBO Rep. 11, 133–138 (2010).

    CAS  PubMed  Google Scholar 

  192. 192.

    Yasukawa, K. et al. Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci. Signal. 2, ra47 (2009).

    PubMed  Google Scholar 

  193. 193.

    Koshiba, T., Yasukawa, K., Yanagi, Y. & Kawabata, S. Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling. Sci. Signal. 4, ra7 (2011).

    PubMed  Google Scholar 

  194. 194.

    Horner, S. M., Liu, H. M., Park, H. S., Briley, J. & Gale, M. Jr. Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus. Proc. Natl Acad. Sci. USA 108, 14590–14595 (2011).

    CAS  PubMed  Google Scholar 

  195. 195.

    Dixit, E. et al. Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141, 668–681 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    de Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).

    PubMed  Google Scholar 

  197. 197.

    Sugiura, A. et al. MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol. Cell 51, 20–34 (2013).

    CAS  PubMed  Google Scholar 

  198. 198.

    Schneider, W. M., Chevillotte, M. D. & Rice, C. M. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 32, 513–545 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    Vanpouille-Box, C., Hoffmann, J. A. & Galluzzi, L. Pharmacological modulation of nucleic acid sensors ― therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 18, 845–867 (2019). (2019).

    CAS  PubMed  Google Scholar 

  200. 200.

    Demaria, O. et al. Harnessing innate immunity in cancer therapy. Nature 574, 45–56 (2019).

    CAS  PubMed  Google Scholar 

  201. 201.

    Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    PubMed  PubMed Central  Google Scholar 

  202. 202.

    Vincent, J. et al. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat. Commun. 8, 750 (2017).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Lama, L. et al. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. Nat. Commun. 10, 2261 (2019).

    PubMed  PubMed Central  Google Scholar 

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Correspondence to Andrea Ablasser or Sun Hur.

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A.A. is a shareholder in a company that is developing STING- and cGAS-directed therapeutics.

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Peer review information Jamie D.K. Wilson was the primary editor on this review article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Ablasser, A., Hur, S. Regulation of cGAS- and RLR-mediated immunity to nucleic acids. Nat Immunol 21, 17–29 (2020). https://doi.org/10.1038/s41590-019-0556-1

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