The role of cGAS in innate immunity and beyond

Journal of Molecular Medicine

Volumn 94, Issue 10, 2016, Pages 1085-1093

  Ablasser, Andrea ^a   Gulen, Muhammed F ^a  

^a EPFL   (Switzerland)

Author keywords

DNA sensing; Innate immunity; Type I interferons

Indexed keywords

CELL NUCLEUS DNA; CYCLIC GMP AMP SYNTHASE; INTERFERON; MITOCHONDRIAL DNA; PROTEIN; PROTEIN STING; SYNTHETASE; UNCLASSIFIED DRUG; VIRUS DNA; DNA; MB21D1 PROTEIN, HUMAN; MEMBRANE PROTEIN; MPYS PROTEIN, HUMAN; NUCLEOTIDYLTRANSFERASE;

AUTOIMMUNE DISEASE; AUTOIMMUNITY; HOST RESISTANCE; HUMAN; INFLAMMATION; INNATE IMMUNITY; MICROORGANISM DETECTION; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION; TUMOR IMMUNITY; ANIMAL; IMMUNOLOGY; NEOPLASM;

ANIMALS; AUTOIMMUNITY; DNA; IMMUNITY, INNATE; MEMBRANE PROTEINS; NEOPLASMS; NUCLEOTIDYLTRANSFERASES; SIGNAL TRANSDUCTION;

EID: 84966263763     PISSN: 09462716     EISSN: 14321440     Source Type: Journal    
DOI: 10.1007/s00109-016-1423-2     Document Type: Review

References (70)

1. Wu J, Sun L, Chen X, Du F, Shi H, Chen C, Chen ZJ (2013) Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–830
2. Sun L, Wu J, Du F, Chen X, Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–791
3. Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–792
4. Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE (2011) STING is a direct innate immune sensor of cyclic di-GMP. Nature 478:515–518
5. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Rohl I, Hopfner KP, Ludwig J, Hornung V (2013) cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498:380–384
6. Diner EJ, Burdette DL, Wilson SC, Monroe KM, Kellenberger CA, Hyodo M, Hayakawa Y, Hammond MC, Vance RE (2013) The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep 3:1355–1361
7. Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, Serganov AA, Liu Y, Jones RA, Hartmann G 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 153:1094–1107
8. Zhang X, Shi H, Wu J, Zhang X, Sun L, Chen C, Chen ZJ (2013) Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell 51:226–235
9. Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M, Witte G, Hornung V, Hopfner KP (2013) Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498:332–337
10. Kranzusch PJ, Lee AS, Berger JM, Doudna JA (2013) Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep 3:1362–1368
11. Li X, Shu C, Yi G, Chaton CT, Shelton CL, Diao J, Zuo X, Kao CC, Herr AB, Li P (2013) Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39:1019–1031
12. Zhang X, Wu J, Du F, Xu H, Sun L, Chen Z, Brautigam CA, Zhang X, Chen ZJ (2014) 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
13. Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ (2013) Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341:1390–1394
14. Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B, Eitson JL, Mar KB, Richardson RB, Ratushny AV, Litvak V et al (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505:691–695
15. Kranzusch PJ, Wilson SC, Lee AS, Berger JM, Doudna JA, Vance RE (2015) Ancient origin of cGAS-STING reveals mechanism of universal 2′,3′ cGAMP signaling. Mol Cell 59:891–903
16. Liang Q, Seo GJ, Choi YJ, Kwak MJ, Ge J, Rodgers MA, Shi M, Leslie BJ, Hopfner KP, Ha T et al (2014) Crosstalk between the cGAS DNA sensor and beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228–238
17. Barber GN (2015) STING: infection, inflammation and cancer. Nat Rev Immunol 15:760–770
18. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu YT, Grishin NV et al (2015) Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347:aaa2630
19. Abe T, Barber GN (2014) Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kappaB activation through TBK1. J Virol 88:5328–5341
20. Dobbs N, Burnaevskiy N, Chen D, Gonugunta VK, Alto NM, Yan N (2015) STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18:157–168
21. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, Hornung V (2013) Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503:530–534
22. Bridgeman A, Maelfait J, Davenne T, Partridge T, Peng Y, Mayer A, Dong T, Kaever V, Borrow P, Rehwinkel J (2015) Viruses transfer the antiviral second messenger cGAMP between cells. Science 349:1228–1232
23. Gentili M, Kowal J, Tkach M, Satoh T, Lahaye X, Conrad C, Boyron M, Lombard B, Durand S, Kroemer G et al (2015) Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349:1232–1236
24. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481–485
25. Xia T, Konno H, Ahn J, Barber GN (2016) Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep 14:282–297
26. Seo GJ, Yang A, Tan B, Kim S, Liang Q, Choi Y, Yuan W, Feng P, Park HS, Jung JU (2015) Akt kinase-mediated checkpoint of cGAS DNA sensing pathway. Cell Rep 13:440–449
27. Xia P, Ye B, Wang S, Zhu X, Du Y, Xiong Z, Tian Y, Fan Z (2016) Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat Immunol. doi:10.1038/ni.3356
28. Collins AC, Cai H, Li T, Franco LH, Li XD, Nair VR, Scharn CR, Stamm CE, Levine B, Chen ZJ et al (2015) Cyclic GMP-AMP synthase is an innate immune DNA sensor for mycobacterium tuberculosis. Cell Host Microbe 17:820–828
29. Watson RO, Bell SL, MacDuff DA, Kimmey JM, Diner EJ, Olivas J, Vance RE, Stallings CL, Virgin HW, Cox JS (2015) The cytosolic sensor cGAS detects mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe 17:811–819
30. Konno H, Konno K, Barber GN (2013) Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155:688–698
31. Wu JJ, Li W, Shao Y, Avey D, Fu B, Gillen J, Hand T, Ma S, Liu X, Miley W et al (2015) Inhibition of cGAS DNA sensing by a herpesvirus virion protein. Cell Host Microbe 18:333–344
32. Ma Z, Jacobs SR, West JA, Stopford C, Zhang Z, Davis Z, Barber GN, Glaunsinger BA, Dittmer DP, Damania B (2015) Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci U S A 112:E4306–4315
33. Lau L, Gray EE, Brunette RL, Stetson DB (2015) DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 350:568–571
34. Dansako H, Ueda Y, Okumura N, Satoh S, Sugiyama M, Mizokami M, Ikeda M, Kato N (2016) The cyclic GMP-AMP synthetase-STING signaling pathway is required for both the innate immune response against HBV and the suppression of HBV assembly. FEBS J 283:144–156
35. Dai P, Wang W, Cao H, Avogadri F, Dai L, Drexler I, Joyce JA, Li XD, Chen Z, Merghoub T et al (2014) Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. PLoS Pathog 10:e1003989
36. Lam E, Stein S, Falck-Pedersen E (2014) Adenovirus detection by the cGAS/STING/TBK1 DNA sensing cascade. J Virol 88:974–981
37. Wang IH, Suomalainen M, Andriasyan V, Kilcher S, Mercer J, Neef A, Luedtke NW, Greber UF (2013) Tracking viral genomes in host cells at single-molecule resolution. Cell Host Microbe 14:468–480
38. Horan KA, Hansen K, Jakobsen MR, Holm CK, Soby S, Unterholzner L, Thompson M, West JA, Iversen MB, Rasmussen SB et al (2013) Proteasomal degradation of herpes simplex virus capsids in macrophages releases DNA to the cytosol for recognition by DNA sensors. J Immunol 190:2311–2319
39. Gao D, Wu J, Wu YT, Du F, Aroh C, Yan N, Sun L, Chen ZJ (2013) Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–906
40. Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C, Hilditch L, Jacques DA, Selwood DL, James LC, Noursadeghi M et al (2013) HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503:402–405
41. Lahaye X, Satoh T, Gentili M, Cerboni S, Conrad C, Hurbain I, El Marjou A, Lacabaratz C, Lelievre JD, Manel N (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 39:1132–1142
42. Herzner AM, Hagmann CA, Goldeck M, Wolter S, Kubler K, Wittmann S, Gramberg T, Andreeva L, Hopfner KP, Mertens C et al (2015) 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
43. Wassermann R, Gulen MF, Sala C, Perin SG, Lou Y, Rybniker J, Schmid-Burgk JL, Schmidt T, Hornung V, Cole ST et al (2015) Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe 17:799–810
44. Man SM, Karki R, Malireddi RK, Neale G, Vogel P, Yamamoto M, Lamkanfi M, Kanneganti TD (2015) The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat Immunol 16:467–475
45. Storek KM, Gertsvolf NA, Ohlson MB, Monack DM (2015) cGAS and Ifi204 cooperate to produce type I IFNs in response to Francisella infection. J Immunol 194:3236–3245
46. Zhang Y, Yeruva L, Marinov A, Prantner D, Wyrick PB, Lupashin V, Nagarajan UM (2014) The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-beta during Chlamydia trachomatis infection. J Immunol 193:2394–2404
47. West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA et al (2015) Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:553–557
48. White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC, Herold MJ, van Delft MF, Bedoui S, Lessene G, Ritchie ME et al (2014) Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159:1549–1562
49. Rongvaux A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY et al (2014) Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159:1563–1577
50. Hartlova A, Erttmann SF, Raffi FA, Schmalz AM, Resch U, Anugula S, Lienenklaus S, Nilsson LM, Kroger A, Nilsson JA et al (2015) DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity 42:332–343
51. Zeng M, Hu Z, Shi X, Li X, Zhan X, Li XD, Wang J, Choi JH, Wang KW, Purrington T et al (2014) MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346:1486–1492
52. Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V (2014) TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol 192:5993–5997
53. Gao D, Li T, Li XD, Chen X, Li QZ, Wight-Carter M, Chen ZJ (2015) Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci U S A 112:E5699–5705
54. Gray EE, Treuting PM, Woodward JJ, Stetson DB (2015) Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of aicardi-goutieres syndrome. J Immunol 195:1939–1943
55. Crow YJ, Manel N (2015) Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol 15:429–440
56. Pokatayev V, Hasin N, Chon H, Cerritelli SM, Sakhuja K, Ward JM, Morris HD, Yan N, Crouch RJ (2016) RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J Exp Med. doi:10.1084/jem.20151464
57. Mackenzie KJ, Carroll P, Lettice L, Tarnauskaite Z, Reddy K, Dix F, Revuelta A, Abbondati E, Rigby RE, Rabe B et al (2016) Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J. doi:10.15252/embj.201593339
58. Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S (2005) Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat Immunol 6:49–56
59. Lan YY, Londono D, Bouley R, Rooney MS, Hacohen N (2014) Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep 9:180–192
60. Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H, Nagata S (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443:998–1002
61. Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ (2016) Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 22:146–153
62. Sharma S, Campbell AM, Chan J, Schattgen SA, Orlowski GM, Nayar R, Huyler AH, Nundel K, Mohan C, Berg LJ et al (2015) Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc Natl Acad Sci U S A 112:E710–717
63. Lemos H, Huang L, Chandler PR, Mohamed E, Souza GR, Li L, Pacholczyk G, Barber GN, Hayakawa Y, Munn DH et al (2014) Activation of the STING adaptor attenuates experimental autoimmune encephalitis. J Immunol 192:5571–5578
64. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS et al (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518
65. Jeremiah N, Neven B, Gentili M, Callebaut I, Maschalidi S, Stolzenberg MC, Goudin N, Fremond ML, Nitschke P, Molina TJ et al (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest 124:5516–5520
66. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li XD, Mauceri H, Beckett M, Darga T et al (2014) STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843–852
67. Ahn J, Xia T, Konno H, Konno K, Ruiz P, Barber GN (2014) Inflammation-driven carcinogenesis is mediated through STING. Nat Commun 5:5166
68. Shen YJ, Le Bert N, Chitre AA, Koo CX, Nga XH, Ho SS, Khatoo M, Tan NY, Ishii KJ, Gasser S (2015) Genome-derived cytosolic DNA mediates type I interferon-dependent rejection of B cell lymphoma cells. Cell Rep 11:460–473
69. Ahn J, Konno H, Barber GN (2015) Diverse roles of STING-dependent signaling on the development of cancer. Oncogene 34:5302–5308
70. Zhu Q, Man SM, Gurung P, Liu Z, Vogel P, Lamkanfi M, Kanneganti TD (2014) Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J Immunol 193:4779–4782