DNA sensor cGAS-mediated immune recognition

Abstract

The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

Keywords

cGAS / cGAMP / innate immunity / cytosolic DNAs / DNA sensors

References

[1] Abdullah Z, Knolle PA (2014) Scalingof immune responses against intracellular bacterial infection. EMBOJ 33:2283–2294

[2] Abe T, Harashima A, Xia T, Konno H, Konno K, Morales A, Ahn J, Gutman D, Barber GN(2013) STING recognition of cytoplasmic DNA instigates cellular defense. Mol Cell 50:5–15

[3] Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V (2009) RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol 10:1065–1072

[4] Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Rohl I, Hopfner KP, Ludwig J, Hornung V (2013a) cGAS producesa2′5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498:380–384

[5] Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, Hornung V (2013b) Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503:530–534

[6] 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

[7] Ahn J, Barber GN (2014) Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. Curr Opin Immunol 31:121–126

[8] Andrade WA, Firon A, Schmidt T, Hornung V, Fitzgerald KA, Kurt-Jones EA, Trieu-Cuot P, Golenbock DT, Kaminski PA (2016) Group B streptococcus degrades cyclic-di-AMP to modulate STING-dependent typeIinterferon production. Cell Host Microbe 20:49–59

[9] Andrews NW (2005) Membrane repair and immunological danger. EMBO Rep 6:826–830

[10] Auerbuch V, Brockstedt DG, Meyer-Morse N, O’Riordan M, Portnoy DA (2004) Mice lacking the typeIinterferon receptor are resistant to Listeria monocytogenes. J Exp Med 200:527–533

[11] Bangert A, Andrassy M, Muller AM, Bockstahler M, Fischer A, Volz CH, Leib C, Goser S, Korkmaz-Icoz S, Zittrich S (2016) Critical role of RAGE and HMGB1 in inflammatory heart disease. Proc Natl Acad Sci USA 113:E155–E164

[12] Beachboard DC, Horner SM (2016) Innate immune evasion strategies of DNA and RNA viruses. Curr Opin Microbiol 32:113–119

[13] 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

[14] Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST (1999) Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285:732–736

[15] Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL (2009) An orthogonal proteomic-genomic screen identifies AIM2 asa cytoplasmic DNA sensor for the inflammasome. Nat Immunol 10:266–272

[16] Burdette DL, Vance RE (2013) STING and the innate immune response to nucleic acids in the cytosol. Nat Immunol 14:19–26

[17] Carroll EC, Jin L, Mori A, Munoz-Wolf N, Oleszycka E, Moran HB, Mansouri S, McEntee CP, Lambe E, Agger EM (2016) The vaccine adjuvant Chitosan promotes cellular immunity via DNA sensor cGAS-STING-dependent induction of type I interferons. Immunity 44:597–608

[18] Cerritelli SM, Crouch RJ (2009) Ribonuclease H: the enzymes in eukaryotes. FEBSJ 276:1494–1505

[19] Chan YK, Gack MU (2016) Viral evasion of intracellular DNA and RNA sensing. Nat Rev Microbiol 14:360–373

[20] Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, Jacob LS, Patwa R, Shah H, Xu K (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493–498

[21] Chiu YH, Macmillan JB, Chen ZJ (2009) RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138:576–591

[22] Civril F, Deimling T, de Oliveira Mann C C, Ablasser A, Moldt M, Witte G, Hornung V, Hopfner KP (2013) Structural mechanismof cytosolic DNA sensing by cGAS. Nature 498:332–337

[23] Collins AC, Cai H, Li T, Franco LH, Li XD, Nair VR, Scharn CR, Stamm CE, Levine B, Chen ZJ (2015) Cyclic GMP-AMP synthase is an innate immune DNA sensor for mycobacterium tuberculosis. Cell Host Microbe 17:820–828

[24] Crawford ED, Seaman JE, Agard N, Hsu GW, Julien O, Mahrus S, Nguyen H, Shimbo K, Yoshihara HA, Zhuang M(2013) The DegraBase: a database of proteolysis in healthy and apoptotic human cells. Mol Cell Proteomics 12:813–824

[25] Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC (2006) Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutieres syndrome at the AGS1 locus. Nat Genet 38:917–920

[26] Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, Oojageer A, Anderson B, Pizzino A, Helman G (2015) Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A 167A:296–312

[27] De Leon J, Jiang G, Ma Y, Rubin E, Fortune S, Sun J (2012) Mycobacterium tuberculosis ESAT-6 exhibits a unique membrane-interacting activity that is not found in its ortholog from non-pathogenic Mycobacterium smegmatis. J Biol Chem 287: 44184–44191

[28] Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, Li XD, Mauceri H, Beckett M, Darga T (2014) STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41:843–852

[29] Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, Lee H, Arthur CD, White JM, Kalinke U (2011) Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med 208:1989–2003

[30] Esbjornsson J, Mansson F, Kvist A, Isberg PE, Nowroozalizadeh S, Biague AJ, da Silva ZJ, Jansson M, Fenyo EM, Norrgren H (2012) Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection. N Engl J Med 367:224–232

[31] Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458:509–513

[32] Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, Gajewski TF (2011) Host type I IFN signals are required for antitumor CD8+Tcell responses through CD8{alpha}+ dendritic cells. J Exp Med 208:2005–2016

[33] Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25:268–276

[34] Gao D, Wu J, Wu YT, Du F, Aroh C, Yan N, Sun L, Chen ZJ (2013a) Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–906

[35] Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, Serganov AA, Liu Y, Jones RA, Hartmann G (2013b) 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

[36] 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 USA 112: E5699–E5705

[37] Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assemblyand localization of Toll-like receptor signalling complexes. Nat Rev Immunol 14:546–558

[38] Gentili M, Kowal J, Tkach M, Satoh T, Lahaye X, Conrad C, Boyron M, Lombard B, Durand S, Kroemer G(2015)Transmissionof innate immune signaling by packaging of cGAMP in viral particles. Science 349:1232–1236

[39] Gong YN, Shao F (2012) Sensing bacterial infections by NAIP receptors in NLRC4 inflammasome activation. Protein Cell 3: 98–105

[40] 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

[41] Gunther C, Kind B, Reijns MA, Berndt N, Martinez-Bueno M, Wolf C, Tungler V, Chara O, Lee YA, Hubner N (2015) Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest 125:413–424

[42] Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial flagellinis mediatedbyToll-like receptor5. Nature 410:1099–1103

[43] Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745

[44] Herzner AM, Hagmann CA, Goldeck M, Wolter S, Kubler K, Wittmann S, Gramberg T, Andreeva L, Hopfner KP, Mertens C (2015) Sequence-specific activation of the DNA sensor cGASbyY-form DNA structures as foundin primary HIV-1 cDNA. Nat Immunol 16:1025–1033

[45] Holm CK, Paludan SR, Fitzgerald KA (2013) DNA recognition in immunity and disease. Curr Opin Immunol 25:13–18

[46] Hornung V (2014) SnapShot: Nucleic acid immune sensors, part 2. Immunity 41(1066–1066):e1061

[47] Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514–518

[48] Hornung V, Hartmann R, Ablasser A, Hopfner KP (2014) OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids. Nat Rev Immunol 14:521–528

[49] Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, Florens L, Washburn MP, Skowronski J (2011) Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474:658–661

[50] Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, Uematsu S, Takeuchi O, Takeshita F, Coban C (2008) TANKbinding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451:725–729

[51] Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–678

[52] Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–792

[53] Jin L, Waterman PM, Jonscher KR, Short CM, Reisdorph NA, Cambier JC (2008) MPYS, a novel membrane tetraspanner, is associated with majorhistocompatibility complexclassII and mediatestransduction ofapoptotic signals. MolCellBiol 28:5014–5026

[54] Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012)Aprogrammable dual-RNA-guided DNA endonucleasein adaptive bacterial immunity. Science 337:816–821

[55] Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O (2005) Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28

[56] Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

[57] Kedes DH, Lagunoff M, Renne R, Ganem D (1997) Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi’s sarcoma-associated herpesvirus. J Clin Invest 100:2606–2610

[58] Kim T, Pazhoor S, Bao M, Zhang Z, Hanabuchi S, Facchinetti V, Bover L, Plumas J, Chaperot L, Qin J (2010) Aspartateglutamate-alanine-histidine box motif (DEAH)/RNA helicase A helicases sense microbial DNA in human plasmacytoid dendritic cells. Proc Natl Acad Sci USA 107:15181–15186

[59] Kirschning CJ, Wesche H, Merrill Ayres T, Rothe M (1998) Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med 188:2091–2097

[60] Kouzaki H, Iijima K, Kobayashi T, O’Grady SM, Kita H (2011) The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses. J Immunol 186:4375–4387

[61] 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

[62] Krieg AM (2003) CpG motifs: the active ingredient in bacterial extracts? Nat Med 9:831–835

[63] Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Segeral E, Yatim A, Emiliani S, Schwartz O, Benkirane M (2011) SAMHD1 is the dendritic-and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474:654–657

[64] 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

[65] Lau L, Gray EE, Brunette RL, Stetson DB (2015) DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 350:568–571

[66] Lauw FN, Caffrey DR, Golenbock DT (2005) Of mice and man: TLR11(finally) finds profilin. Trends Immunol 26:509–511

[67] Leung DW, Amarasinghe GK (2016) When your cap matters: structural insightsinto selfvs non-self recognitionof5’ RNA by immunomodulatory host proteins. Curr Opin Struct Biol 36:133–141

[68] Li Y, Chen R, Zhou Q, Xu Z, Li C, Wang S, Mao A, Zhang X, He W, Shu HB (2012) LSm14A is a processing body-associated sensor of viral nucleic acids that initiates cellular antiviral response in the early phase of viral infection. Proc Natl Acad Sci USA 109: 11770–11775

[69] Li X, Shu C, Yi G, Chaton CT, Shelton CL, Diao J, Zuo X, Kao CC, Herr AB, Li P (2013a) Cyclic GMP-AMP synthaseis activatedby double-stranded DNA-induced oligomerization. Immunity 39:1019–1031

[70] Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ (2013b) Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341:1390–1394

[71] Liang Q, Seo GJ, Choi YJ, Kwak MJ, Ge J, Rodgers MA, Shi M, Leslie BJ, Hopfner KP, Ha T (2014) Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15:228–238

[72] Lindahl T, Wood RD (1999) Quality control by DNA repair. Science 286:1897–1905

[73] Lu C, Xu H, Ranjith-Kumar CT, Brooks MT, Hou TY, Hu F, Herr AB, Strong RK, Kao CC, Li P (2010) The structural basis of 5′ triphosphate double-stranded RNA recognition by RIG-I C-terminal domain. Structure 18:1032–1043

[74] Ma Z, Damania B(2016) The cGAS-STING defense pathway and its counteraction by viruses. Cell Host Microbe 19:150–158

[75] 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 USA 112:E4306–E4315

[76] Manel N, Hogstad B, Wang Y, Levy DE, Unutmaz D, Littman DR (2010) A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467:214–217

[77] Mankan AK, Schmidt T, Chauhan D, Goldeck M, Honing K, Gaidt M, Kubarenko AV, Andreeva L, Hopfner KP, Hornung V (2014) Cytosolic RNA:DNA hybrids activate the cGAS-STING axis. EMBOJ 33:2937–2946

[78] Manzanillo PS, Shiloh MU, Portnoy DA, Cox JS (2012) Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages. Cell Host Microbe 11:469–480

[79] Marq JB, Hausmann S, Veillard N, Kolakofsky D, Garcin D (2011) Short double-stranded RNAs with an overhanging 5’ pppnucleotide, as found in arenavirus genomes, act as RIG-I decoys. J Biol Chem 286:6108–6116

[80] McCurdy JD, Olynych TJ, Maher LH, Marshall JS (2003) Cutting edge: distinct Toll-like receptor 2 activators selectively induce different classes of mediator production from human mast cells. J Immunol 170:1625–1629

[81] McLaughlin-Drubin ME, Munger K(2009) The human papillomavirus E7 oncoprotein. Virology 384:335–344

[82] Mizel SB, West AP, Hantgan RR (2003) Identification of a sequence in human toll-like receptor 5 required for the binding of Gram-negative flagellin. J Biol Chem 278:23624–23629

[83] Monroe KM, Yang Z, Johnson JR, Geng X, Doitsh G, Krogan NJ, Greene WC (2014) IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343:428–432

[84] Morita M, Stamp G, Robins P, Dulic A, Rosewell I, Hrivnak G, Daly G, Lindahl T, Barnes DE (2004) Gene-targeted mice lacking the Trex1 (DNase III)3′–>5′ DNA exonuclease develop inflammatory myocarditis. Mol Cell Biol 24:6719–6727

[85] Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, Parks RJ, Tschopp J (2008) The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452:103–107

[86] Nick McElhinny SA, Watts BE, Kumar D, Watt DL, Lundstrom EB, Burgers PM, Johansson E, Chabes A, Kunkel TA (2010) Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases. Proc Natl Acad Sci USA 107:4949–4954

[87] O’Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, Perry AK, Nguyen BO, Lane TF, Taniguchi T (2004) Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med 200:437–445

[88] Orzalli MH, DeLuca NA, Knipe DM (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–E3017

[89] Orzalli MH, Broekema NM, Diner BA, Hancks DC, Elde NC, Cristea IM, Knipe DM (2015) cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. Proc Natl Acad Sci USA 112:E1773–E1781

[90] Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A (2000) The repertoire for pattern recognitionof pathogensbythe innate immune systemisdefined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 97:13766–13771

[91] Paludan SR, Bowie AG (2013) Immune sensing of DNA. Immunity 38:870–880

[92] 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 213:329–336

[93] Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C(1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088

[94] Rongvaux A, Jackson R, Harman CC, Li T, West AP, de Zoete MR, Wu Y, Yordy B, Lakhani SA, Kuan CY (2014) Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159:1563–1577

[95] Saito T, Gale M Jr (2007) Principles of intracellular viral recognition. Curr Opin Immunol 19:17–23

[96] Sampson TR, Saroj SD, Llewellyn AC, Tzeng YL, Weiss DS (2013) A CRISPR/Cas system mediates bacterial innate immune evasion and virulence. Nature 497:254–257

[97] Schoggins JW, Rice CM (2011) Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol 1:519–525

[98] Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) Adiverse rangeof gene products are effectors of the typeI interferon antiviral response. Nature 472:481–485

[99] Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B, Eitson JL, Mar KB, Richardson RB, Ratushny AV, Litvak V (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505:691–695

[100] Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ (1999) Peptidoglycan-and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 274: 17406–17409

[101] 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

[102] Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F (2014) Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514:187–192

[103] Shu C, Yi G, Watts T, Kao CC, Li P(2012) StructureofSTING boundto cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognitionbythe immune system. Nat StructMolBiol 19:722–724

[104] Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, Enninga J (2012) Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog 8: e1002507

[105] Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. SciTransl Med 5:200ra116

[106] Sun W, Li Y, Chen L, Chen H, You F, Zhou X, Zhou Y, Zhai Z, Chen D, Jiang Z(2009) ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci USA 106:8653–8658

[107] 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

[108] Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, Lu Y, Miyagishi M, Kodama T, Honda K(2007) DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448:501–505

[109] Tsunekawa N, Higashi N, Kogane Y, Waki M, Shida H, Nishimura Y, Adachi H, Nakajima M, Irimura T (2016) Heparanase augments inflammatory chemokine production from colorectal carcinoma cell lines. Biochem Biophys Res Commun 469:878–883

[110] Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS (2010) IFI16is an innate immune sensor for intracellular DNA. Nat Immunol 11:997–1004

[111] van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ (2007) M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129:1287–1298

[112] Wang Y, Ludwig J, Schuberth C, Goldeck M, Schlee M, Li H, Juranek S, Sheng G, Micura R, Tuschl T (2010) Structural and functional insights into 5’-ppp RNA pattern recognition by the innate immune receptor RIG-I. Nat Struct Mol Biol 17:781–787

[113] Wassermann R, Gulen MF, Sala C, Perin SG, Lou Y, Rybniker J, Schmid-Burgk JL, Schmidt T, Hornung V, Cole ST (2015) Mycobacterium tuberculosis differentially activates cGAS-and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe 17:799–810

[114] 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

[115] Weber-Gerlach M, Weber F (2016) Standing on three legs: antiviral activities of RIG-I against influenza viruses. Curr Opin Immunol 42:71–75

[116] West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA (2015) Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:553–557

[117] White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC, Herold MJ, van Delft MF, Bedoui S, Lessene G, Ritchie ME (2014) Apoptotic caspases suppress mtDNA-induced STING-mediated typeI IFN production. Cell 159:1549–1562

[118] Whiteley AT, Pollock AJ, Portnoy DA (2015) ThePAMP c-di-AMP Is Essential for Listeria monocytogenes Growth in Rich but Not Minimal MediaduetoaToxic Increasein (p)ppGpp. ［corrected］. Cell Host Microbe 17:788–798

[119] Wick G, Jakic B, Buszko M, Wick MC, Grundtman C (2014) Theroleof heat shock proteins in atherosclerosis. Nat Rev Cardiol 11:516–529

[120] Wilkins C, Gale M Jr (2010) Recognition of viruses by cytoplasmic sensors. Curr Opin Immunol 22:41–47

[121] Wolf C, Rapp A, Berndt N, Staroske W, Schuster M, Dobrick-Mattheuer M, Kretschmer S, Konig N, Kurth T, Wieczorek D (2016) RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA. Nat Commun 7:11752

[122] Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, Duggan R, Wang Y, Barber GN, Fitzgerald KA (2014) STINGdependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–842

[123] Wu J, Chen ZJ (2014) Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol 32:461–488

[124] 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

[125] Wu JJ, Li W, Shao Y, Avey D, Fu B, Gillen J, Hand T, Ma S, Liu X, Miley W (2015) Inhibition of cGAS DNA sensing by a herpesvirus virion protein. Cell Host Microbe 18:333–344

[126] Xia P, Wang S, Ye B, Du Y, Huang G, Zhu P, Fan Z (2015) Sox2 functions as a sequence-specific DNA sensor in neutrophils to initiate innate immunity against microbial infection. Nat Immunol 16:366–375

[127] Xia P, Ye B, Wang S, Zhu X, Du Y, Xiong Z, Tian Y, Fan Z (2016) Glutamylation ofthe DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat Immunol 17:369–378

[128] Yang YG, LindahlT, Barnes DE (2007) Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–886

[129] Yang P, An H, Liu X, Wen M, Zheng Y, Rui Y, Cao X (2010) The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a beta-catenin-dependent pathway. Nat Immunol 11:487–494

[130] Yang J, Zhao Y, Shao F (2015) Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity. Curr Opin Immunol 32:78–83

[131] Yin Q, Fu TM, Li J, Wu H (2015) Structural biology of innate immunity. Annu Rev Immunol 33:393–416

[132] Yoh SM, Schneider M, Seifried J, Soonthornvacharin S, Akleh RE, Olivieri KC, De Jesus PD, Ruan C, de Castro E, Ruiz PA (2015) PQBP1 is a proximal sensor of the cGAS-dependent innate response to HIV-1. Cell 161:1293–1305

[133] Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T (2004) The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737

[134] Zhang FX, Kirschning CJ, Mancinelli R, Xu XP, Jin Y, Faure E, Mantovani A, Rothe M, Muzio M, Arditi M (1999) Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 274:7611–7614

[135] Zhang X, Brann TW, Zhou M, Yang J, Oguariri RM, Lidie KB, Imamichi H, Huang DW, Lempicki RA, Baseler MW (2011a) Cutting edge: Ku70 is a novel cytosolic DNA sensor that induces type III rather than typeI IFN. J Immunol 186:4541–4545

[136] Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ (2011b) The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 12:959–965

[137] 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

[138] 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

[139] Zhang G, Chan B, Samarina N, Abere B, Weidner-Glunde M, Buch A, Pich A, Brinkmann MM, Schulz TF (2016) Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS. Proc Natl Acad Sci USA 113:E1034–E1043

[140] Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, Liu L, Shao F (2011) The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477:596–600

[141] Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P (2008) The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–550

RIGHTS & PERMISSIONS

2016 The Author(s) 2016. This article is published with open access at Springerlink.com and journal.hep.com.cn