Cytosolic sensors of pathogen-associated DNA (Homo sapiens)

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21, 86, 1057, 10157, 8316167, 13, 1469, 9946, 53, 55, 77565663, 81, 923, 10, 12, 25, 41...17, 63, 9045814, 719, 47, 77, 8427, 9862, 89, 92, 9735, 71, 8833, 63, 8130, 7353, 1007, 29563, 9, 11, 15, 34...4669, 9957, 83457, 268343, 9662, 89, 92, 97163, 6739, 46, 5145, 72, 76, 9150, 10224, 7346169816520, 24, 7356461, 78, 85endoplasmic reticulum(perinuclear vesicle)endosomenucleoplasmcytosolcytoplasmic vesicle lumenp-S552-CTNNB1CREBBP TICAM1 TLR3 UBB(77-152) p-S172-TBK1 DHX36:CpGPOLR2F TRIM56 HSV2 dsDNA HSV1 dsDNA UBC(1-76) NFkB ComplexDTX4 STING:STINGK63polyUb-STING TRIM32/TRIM56DHX36 K48polyUb-DDX41 POLR1C UBC(533-608) IRF3 HBV dsDNA ATPHCMV dsDNA HCMV dsDNA PPiUBC(457-532) ADPTRIM21DHX36:CpG:MyD88beta-catenin:IRF3:p300UBC(1-76) TMEM173 K48polyUb-DDX41:TRIM21IRF3 POLR2L POLR3A p-S407,Y641-STAT6dimerUBB(1-76) K63polyUb-STING STING:cGAMPp-S407-STAT6CRCP RPS27A(1-76) HCMV dsDNA DTX4XRCC5 CHUK ZBP1TBK1 DDX41:c-di-AMP,c-di-GMPSTING:p-S172-TBK1:STAT6HCV dsDNA HSV2 dsDNA CTNNB1CREBBP c-di-AMP NLRP4:DTX4:dsDNA:ZBP1:pS-172-TBK1viral plus strand DNA with sticky 3' end UBC(153-228) CTNNB1 XRCC5 ZBP1 RIPK1Rotavirus dsRNA VACV dsDNA viral plus strand DNA with sticky 3' end MYD88 PRKDC UBB(1-76) DDX41 Influenza A dsRNA intermediate form DTX4 IRF3POLR2H dsDNA:ZBP1Phospho-NF-kappaBInhibitorSTING:TRIM32/TRIM56p-T,4S-IRF3:p-T,4S-IRF3ATPUBB(1-76) UBC(153-228) UBC(609-684) RIPK3UbATPL. monocytogenes dsDNA Unmethylated CpG DNA UBC(229-304) DHX9/DHX36:CpGDDX41 viral ligandHSV1 dsDNA IKBKG RNA Polymerase IIIHoloenzymeSTING:c-di-GMPK63polyUb-STING Double-stranded DNA POLR3E LRRFIP1 viral plus strand DNA with sticky 3' end p-S552-CTNNB1 STAT6 IRF3HBV dsRNA intermediate form p-S172-TBK1 DHX9 K63polyUb-STING c-GMP-AMPVACV dsDNA ADPK63polyUb-STING ATPMg2+ MYD88 2'-deoxyadenosine5'-monophosphateRPS27A(1-76) UBB(77-152) p-4S,T404-IRF3RIPK1 ADPUBC(457-532) NFKB1(1-433) K63polyUb-STING TREX1 dimerADPNLRP4 RIPK1 UBB(77-152) 5'-ppp-AU-rich dsRNAUBC(1-76) POLR3D DHX9 viral minus strand DNA with sticky 3' end DHX36 viraldsRNA:TLR3:TICAM1:RIPK1NFKB1(1-433) POLR2K POLR3F dsDNA:ZBP1:pS-172-TBK:IRF3NLRP4HSV2 dsDNA POLR3G DDX41 p-T,4S-IRF3:p-T,4S-IRF3MB21D1UBB(1-76) DHX9:CpG:MyD88p-S407,Y641-STAT6 DHX36 UBA52(1-76) UBC(533-608) UBC(381-456) TBK1L.pneumophila dsDNA H2ORPS27A(1-76) UBC(305-380) HSV1 dsDNA UBC(305-380) cGAS:dsDNATREX1:viral DNAHCMV dsDNA POLR3H HCV dsDNAL. monocytogenes dsDNA UBB(153-228) p-S172-TBK1 NFKB2(1-454) UBC(609-684) IRF3 TRIM32 K63polyUb-STING M. tuberculosis dsDNA LRRFIP1 EBV dsDNA DNA-PK:microbialdsDNACHUK:IKBKB:IKBKGADPHCMV dsDNA UBC(77-152) IFI16c-di-AMP ADPRELA NFKBIB ATPIKBKG viral minus strand DNA with sticky 3' end cGAS ligandsdsDNA:LRRFLII-interactingprotein 1dimerL. monocytogenes dsDNA UBC(457-532) p-4S,T404-IRF3 POLR3C TBK1 ADPHSV1 dsDNA MRE11A ADPTREX1 UBC(609-684) GTPMB21D1 viral minus strand DNA with sticky 3' end UBC(229-304) p-S172-TBK1 viral minus strand DNA with sticky 3' end ATPZBP1 UBC(153-228) UBC(77-152) 2xp-S477,S479-IRF7p-2S-IRF7:p-2S-IRF7CREBBP,EP300NFKB1(1-433),NFKB2(1-454):RELAPOLR3GL p-S407,Y641-STAT6 TMEM173 UBC(381-456) RELA NKIRAS2 RELA UBC(533-608) dsDNA:IFI16UbSTING:p-S172-TBK1UBC(533-608) p-S477,S479-IRF7 LRR FLII-interactingprotein 1 dimerUBC(305-380) EP300 PRKDCSTING:STINGATPc-GMP-AMP TMEM173POLR3B Double-stranded DNAHCV dsRNA intermediate form TRIM56 ZBP1 K63polyUb-STING Unmethylated CpG DNA Mg2+NKIRASHCMV dsDNA viral plus strand DNA with sticky 3' end MYD88 UBC(381-456) dCMPUBC(381-456) VACV dsDNA MRE11:dsDNAviral plus strand DNA with sticky 3' end UBC(153-228) IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBHCMV dsDNA p-S176,S180-CHUK HBV dsDNA p-S552-CTNNB1ATPUBB(153-228) DHX36HSV2 dsDNA MRE11AM. tuberculosis dsDNA ZBP1 UBC(229-304) DHX9HSV1 dsRNA intermediate form IFI16 ligandsUnmethylated CpG DNA p-S177,S181-IKBKB HSV1 dsDNA DHX9/DHX36:CpG:MyD88NLRP4:DTX4:STING:p-S172-TBK1:IRF3VACV dsDNA IRF3 UBB(153-228) UBC(229-304) ATPUBB(77-152) Pol-III ligandsIFI16 Unmethylated CpG DNA viral plus strand DNA with sticky 3' end NKIRAS1 2'-deoxyguanosine5'-monophosphateNLRP4TRIM21 STAT6 HSV2 dsDNA DHX9:CpGDDX58/IFIH1-mediatedinductionofinterferon-alpha/betaTRIM32 viral minus strand DNA with sticky 3' end STING:p-S172,K48polyUb-TBK1:IRF3UBC(305-380) p-4S,T404-IRF3 ZBP1 ligandDHX9 VACV dsDNA NFKB2(1-454) Promotor region ofinterferon betaUBA52(1-76) NFkB inhibitor:NFkBcomplexp-S172-TBK1 DHX9 K63polyUb-STING DHX36 viral minus strand DNA with sticky 3' end DTX4K48polyUb-DDX41 L. monocytogenes dsDNA VACV dsDNA HSV1 dsDNA UbTMPUBC(609-684) NFKB2(1-454) TBK1Unmethylated CpG DNA UBA52(1-76) dsDNA:LRRFIP1:beta-cateninK63polyUb-STING c-di-GMP p-S172-TBK1 STAT6XRCC6 HCV dsDNA p-4S,T404-IRF3 STING:TBK1:IRF3K63polyUb-STINGp-S407,Y641-STAT6RIPK3 c-di-GMP UBC(1-76) IRF3 ZBP1 p-S172-TBK1 ZBP1 UbSTING:p-S172-TBK1:IRF3p-S32,S36-NFKBIA LRRFIP1 NFKB1(1-433) HSV2 dsDNA NLRC3Ku70:Ku80heterodimerHSV1 dsDNA Promotor region of interferon beta c-di-GMP EP300 DDX41:DDX41 ligandPOLR1D UBC(457-532) UBC(77-152) POLR3K UBA52(1-76) pS-172,K48polyUb-TBK1 NLRP4 viral DNA with 3'sticky endsRPS27A(1-76) dsDNA:ZBP1:pS-172,K48polyUb-TBK1POLR2E HSV2 dsDNA IKBKB DNA-PK ligandsMYD88ATPADPUBC(77-152) DDX41c-di-GMPUBB(153-228) XRCC6 dsDNA:ZBP1:pS-172-TBK1pS-172,K48polyUb-TBK1 p-S477,S479-IRF7 TREX1 STING:TBK1:STAT6c-di-AMP, c-di-GMPUnmethylated CpG DNANFKBIA ADPp-S407,Y641-STAT6dimerdsDNA:ZBP1:RIP1:RIP3ATPUnmethylated CpG DNA p-S19,S23-NFKBIB 8773564, 8232096244654, 70397, 382332, 5731654, 70, 946, 57, 59, 66, 75562, 59, 61, 1039218, 36, 37, 48, 68...92838016249922, 4244, 9528, 49, 6531, 984654464620, 2492508, 47, 52


Description

Presence of pathogen-associated DNA in cytosol induces type I IFN production. Several intracellular receptors have been implicated to some degree. These include DNA-dependent activator of interferon (IFN)-regulatory factors (DAI) (also called Z-DNA-binding protein 1, ZBP1), absent in melanoma 2 (AIM2), RNA polymerase III (Pol III), IFN-inducible protein IFI16, leucine-rich repeat flightless interacting protein-1 (LRRFIP1), DEAH-box helicases (DHX9 and DHX36), DEAD-box helicase DDX41, meiotic recombination 11 homolog A (MRE11), DNA-dependent protein kinase (DNA-PK), cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING).

Detection of cytosolic DNA requires multiple and possibly redundant sensors leading to activation of the transcription factor NF-kappaB and TBK1-mediated phosphorylation of the transcription factor IRF3. Cytosolic DNA also activates caspase-1-dependent maturation of the pro-inflammatory cytokines interleukin IL-1beta and IL-18. This pathway is mediated by AIM2. View original pathway at Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1834949
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: Shamovsky, Veronica

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  76. Ha SC, Kim D, Hwang HY, Rich A, Kim YG, Kim KK.; ''The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA reveals an unusual binding mode to Z-DNA.''; PubMed Europe PMC Scholia
  77. Bonizzi G, Karin M.; ''The two NF-kappaB activation pathways and their role in innate and adaptive immunity.''; PubMed Europe PMC Scholia
  78. Li T, Diner BA, Chen J, Cristea IM.; ''Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16.''; PubMed Europe PMC Scholia
  79. Sauer JD, Sotelo-Troha K, von Moltke J, Monroe KM, Rae CS, Brubaker SW, Hyodo M, Hayakawa Y, Woodward JJ, Portnoy DA, Vance RE.; ''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.''; PubMed Europe PMC Scholia
  80. Orebaugh CD, Fye JM, Harvey S, Hollis T, Perrino FW.; ''The TREX1 exonuclease R114H mutation in Aicardi-Goutières syndrome and lupus reveals dimeric structure requirements for DNA degradation activity.''; PubMed Europe PMC Scholia
  81. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T.; ''IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway.''; PubMed Europe PMC Scholia
  82. Liu Y, Zou Z, Zhu B, Hu Z, Zeng P, Wu L.; ''LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes.''; PubMed Europe PMC Scholia
  83. Sun L, Wu J, Du F, Chen X, Chen ZJ.; ''Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.''; PubMed Europe PMC Scholia
  84. Li X, Massa PE, Hanidu A, Peet GW, Aro P, Savitt A, Mische S, Li J, Marcu KB.; ''IKKalpha, IKKbeta, and NEMO/IKKgamma are each required for the NF-kappa B-mediated inflammatory response program.''; PubMed Europe PMC Scholia
  85. Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, Chandran B.; ''IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection.''; PubMed Europe PMC Scholia
  86. Sharma S, Fitzgerald KA.; ''Innate immune sensing of DNA.''; PubMed Europe PMC Scholia
  87. Son KN, Liang Z, Lipton HL.; ''Double-Stranded RNA Is Detected by Immunofluorescence Analysis in RNA and DNA Virus Infections, Including Those by Negative-Stranded RNA Viruses.''; PubMed Europe PMC Scholia
  88. Gil J, Alcamí J, Esteban M.; ''Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex.''; PubMed Europe PMC Scholia
  89. Ma X, Helgason E, Phung QT, Quan CL, Iyer RS, Lee MW, Bowman KK, Starovasnik MA, Dueber EC.; ''Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation.''; PubMed Europe PMC Scholia
  90. Servant MJ, ten Oever B, LePage C, Conti L, Gessani S, Julkunen I, Lin R, Hiscott J.; ''Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3.''; PubMed Europe PMC Scholia
  91. Wang Z, Choi MK, Ban T, Yanai H, Negishi H, Lu Y, Tamura T, Takaoka A, Nishikura K, Taniguchi T.; ''Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules.''; PubMed Europe PMC Scholia
  92. Tanaka Y, Chen ZJ.; ''STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.''; PubMed Europe PMC Scholia
  93. Bowie AG, Unterholzner L.; ''Viral evasion and subversion of pattern-recognition receptor signalling.''; PubMed Europe PMC Scholia
  94. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC Scholia
  95. Qin BY, Liu C, Lam SS, Srinath H, Delston R, Correia JJ, Derynck R, Lin K.; ''Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation.''; PubMed Europe PMC Scholia
  96. Ferguson BJ, Mansur DS, Peters NE, Ren H, Smith GL.; ''DNA-PK is a DNA sensor for IRF-3-dependent innate immunity.''; PubMed Europe PMC Scholia
  97. Clark K, Plater L, Peggie M, Cohen P.; ''Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation.''; PubMed Europe PMC Scholia
  98. Yan N, Regalado-Magdos AD, Stiggelbout B, Lee-Kirsch MA, Lieberman J.; ''The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1.''; PubMed Europe PMC Scholia
  99. Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S.; ''The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA.''; PubMed Europe PMC Scholia
  100. Kaiser WJ, Upton JW, Mocarski ES.; ''Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors.''; PubMed Europe PMC Scholia
  101. Lee YH, Stallcup MR.; ''Interplay of Fli-I and FLAP1 for regulation of beta-catenin dependent transcription.''; PubMed Europe PMC Scholia
  102. Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V.; ''RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate.''; PubMed Europe PMC Scholia
  103. Jakobsen MR, Bak RO, Andersen A, Berg RK, Jensen SB, Tengchuan J, Laustsen A, Hansen K, Ostergaard L, Fitzgerald KA, Xiao TS, Mikkelsen JG, Mogensen TH, Paludan SR.; ''IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication.''; PubMed Europe PMC Scholia
  104. Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, Matsunaga K, Kageyama S, Omori H, Noda T, Yamamoto N, Kawai T, Ishii K, Takeuchi O, Yoshimori T, Akira S.; ''Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response.''; PubMed Europe PMC Scholia
  105. Paludan SR, Bowie AG.; ''Immune sensing of DNA.''; PubMed Europe PMC Scholia
  106. Sun W, Li Y, Chen L, Chen H, You F, Zhou X, Zhou Y, Zhai Z, Chen D, Jiang Z.; ''ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
112538view15:50, 9 October 2020ReactomeTeamReactome version 73
101451view11:32, 1 November 2018ReactomeTeamreactome version 66
100989view21:10, 31 October 2018ReactomeTeamreactome version 65
100525view19:44, 31 October 2018ReactomeTeamreactome version 64
100072view16:28, 31 October 2018ReactomeTeamreactome version 63
99623view15:01, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99230view12:44, 31 October 2018ReactomeTeamreactome version 62
94006view13:50, 16 August 2017ReactomeTeamreactome version 61
93618view11:28, 9 August 2017ReactomeTeamreactome version 61
87165view19:20, 18 July 2016MkutmonOntology Term : 'immune response pathway' added !
86726view09:24, 11 July 2016ReactomeTeamreactome version 56
83421view11:11, 18 November 2015ReactomeTeamVersion54
81624view13:10, 21 August 2015ReactomeTeamVersion53
77085view08:38, 17 July 2014ReactomeTeamFixed remaining interactions
76790view12:15, 16 July 2014ReactomeTeamFixed remaining interactions
76113view10:17, 11 June 2014ReactomeTeamRe-fixing comment source
75825view11:38, 10 June 2014ReactomeTeamReactome 48 Update
75187view09:37, 9 May 2014AnweshaFixing comment source for displaying WikiPathways description
74826view10:04, 30 April 2014ReactomeTeamReactome46
74822view08:55, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2'-deoxyadenosine 5'-monophosphateMetaboliteCHEBI:17713 (ChEBI)
2'-deoxyguanosine 5'-monophosphateMetaboliteCHEBI:16192 (ChEBI)
2xp-S477,S479-IRF7ComplexR-HSA-450306 (Reactome)
5'-ppp-AU-rich dsRNAR-ALL-1964477 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
CRCP ProteinO75575 (Uniprot-TrEMBL)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBP,EP300ComplexR-HSA-1027362 (Reactome)
CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
CTNNB1ProteinP35222 (Uniprot-TrEMBL)
DDX41 ProteinQ9UJV9 (Uniprot-TrEMBL)
DDX41 viral ligandComplexR-NUL-9015688 (Reactome)
DDX41:DDX41 ligandComplexR-HSA-3134844 (Reactome)
DDX41:c-di-AMP, c-di-GMPComplexR-HSA-9013866 (Reactome)
DDX41ProteinQ9UJV9 (Uniprot-TrEMBL)
DDX58/IFIH1-mediated

induction of

interferon-alpha/beta
PathwayR-HSA-168928 (Reactome) RIG-I-like helicases (RLHs) the retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) are RNA helicases that recognize viral RNA present within the cytoplasm. Functionally RIG-I and MDA5 positively regulate the IFN genes in a similar fashion, however they differ in their response to different viral species. RIG-I is essential for detecting influenza virus, Sendai virus, VSV and Japanese encephalitis virus (JEV), whereas MDA5 is essential in sensing encephalomyocarditis virus (EMCV), Mengo virus and Theiler's virus, all of which belong to the picornavirus family. RIG-I and MDA5 signalling results in the activation of IKK epsilon and (TKK binding kinase 1) TBK1, two serine/threonine kinases that phosphorylate interferon regulatory factor 3 and 7 (IRF3 and IRF7). Upon phosphorylation, IRF3 and IRF7 translocate to the nucleus and subsequently induce interferon alpha (IFNA) and interferon beta (IFNB) gene transcription.
DHX36 ProteinQ9H2U1 (Uniprot-TrEMBL)
DHX36:CpG:MyD88ComplexR-HSA-3134859 (Reactome)
DHX36:CpGComplexR-HSA-3134858 (Reactome)
DHX36ProteinQ9H2U1 (Uniprot-TrEMBL)
DHX9 ProteinQ08211 (Uniprot-TrEMBL)
DHX9/DHX36:CpG:MyD88ComplexR-HSA-3134961 (Reactome)
DHX9/DHX36:CpGComplexR-HSA-3134958 (Reactome)
DHX9:CpG:MyD88ComplexR-HSA-3134868 (Reactome)
DHX9:CpGComplexR-HSA-3134960 (Reactome)
DHX9ProteinQ08211 (Uniprot-TrEMBL)
DNA-PK ligandsComplexR-NUL-9013760 (Reactome)
DNA-PK:microbial dsDNAComplexR-HSA-3134811 (Reactome)
DTX4 ProteinQ9Y2E6 (Uniprot-TrEMBL)
DTX4ProteinQ9Y2E6 (Uniprot-TrEMBL)
Double-stranded DNA MetaboliteCHEBI:16991 (ChEBI)
Double-stranded DNAMetaboliteCHEBI:16991 (ChEBI)
EBV dsDNA R-HGA-9013852 (Reactome)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HBV dsDNA R-HBV-9013761 (Reactome)
HBV dsRNA intermediate form R-HBV-8982481 (Reactome)
HCMV dsDNA R-HCY-8982093 (Reactome)
HCV dsDNA R-HCV-9013817 (Reactome)
HCV dsDNAR-HCV-9013817 (Reactome)
HCV dsRNA intermediate form R-HCV-8982462 (Reactome)
HSV1 dsDNA R-HER-8982066 (Reactome)
HSV1 dsRNA intermediate form R-HER-6791257 (Reactome)
HSV2 dsDNA R-HAL-8982085 (Reactome)
IFI16 ProteinQ16666 (Uniprot-TrEMBL)
IFI16 ligandsComplexR-NUL-9013802 (Reactome)
IFI16ProteinQ16666 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBComplexR-HSA-177663 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF3ProteinQ14653 (Uniprot-TrEMBL)
Influenza A dsRNA intermediate form R-FLU-9028895 (Reactome)
K48polyUb-DDX41 ProteinQ9UJV9 (Uniprot-TrEMBL)
K48polyUb-DDX41:TRIM21ComplexR-HSA-3134947 (Reactome)
K63polyUb-STING ProteinQ86WV6 (Uniprot-TrEMBL)
K63polyUb-STINGProteinQ86WV6 (Uniprot-TrEMBL)
Ku70:Ku80 heterodimerComplexR-HSA-3134809 (Reactome)
L. monocytogenes dsDNA R-LMO-8982051 (Reactome)
L.pneumophila dsDNA R-LPN-9013849 (Reactome)
LRR FLII-interacting protein 1 dimerComplexR-HSA-3134884 (Reactome)
LRRFIP1 ProteinQ32MZ4 (Uniprot-TrEMBL)
M. tuberculosis dsDNA R-MTU-8982063 (Reactome)
MB21D1 ProteinQ8N884 (Uniprot-TrEMBL)
MB21D1ProteinQ8N884 (Uniprot-TrEMBL)
MRE11:dsDNAComplexR-HSA-3204308 (Reactome)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRE11AProteinP49959 (Uniprot-TrEMBL)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88ProteinQ99836 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mg2+MetaboliteCHEBI:18420 (ChEBI)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKB1(1-433), NFKB2(1-454):RELAComplexR-HSA-168155 (Reactome)
NFKB2(1-454) ProteinQ00653 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
NFkB ComplexComplexR-HSA-177673 (Reactome)
NFkB inhibitor:NFkB complexComplexR-HSA-168130 (Reactome)
NKIRAS1 ProteinQ9NYS0 (Uniprot-TrEMBL)
NKIRAS2 ProteinQ9NYR9 (Uniprot-TrEMBL)
NKIRASComplexR-HSA-8952687 (Reactome)
NLRC3ProteinQ7RTR2 (Uniprot-TrEMBL)
NLRP4 ProteinQ96MN2 (Uniprot-TrEMBL)
NLRP4:DTX4:STING:p-S172-TBK1:IRF3ComplexR-HSA-8948707 (Reactome)
NLRP4:DTX4:dsDNA:ZBP1:pS-172-TBK1ComplexR-HSA-3249384 (Reactome)
NLRP4ProteinQ96MN2 (Uniprot-TrEMBL)
POLR1C ProteinO15160 (Uniprot-TrEMBL)
POLR1D ProteinP0DPB5 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2F ProteinP61218 (Uniprot-TrEMBL)
POLR2H ProteinP52434 (Uniprot-TrEMBL)
POLR2K ProteinP53803 (Uniprot-TrEMBL)
POLR2L ProteinP62875 (Uniprot-TrEMBL)
POLR3A ProteinO14802 (Uniprot-TrEMBL)
POLR3B ProteinQ9NW08 (Uniprot-TrEMBL)
POLR3C ProteinQ9BUI4 (Uniprot-TrEMBL)
POLR3D ProteinP05423 (Uniprot-TrEMBL)
POLR3E ProteinQ9NVU0 (Uniprot-TrEMBL)
POLR3F ProteinQ9H1D9 (Uniprot-TrEMBL)
POLR3G ProteinO15318 (Uniprot-TrEMBL)
POLR3GL ProteinQ9BT43 (Uniprot-TrEMBL)
POLR3H ProteinQ9Y535 (Uniprot-TrEMBL)
POLR3K ProteinQ9Y2Y1 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKDC ProteinP78527 (Uniprot-TrEMBL)
PRKDCProteinP78527 (Uniprot-TrEMBL)
Phospho-NF-kappaB InhibitorComplexR-HSA-177678 (Reactome)
Pol-III ligandsComplexR-NUL-9013853 (Reactome)
Promotor region of interferon betaR-ALL-1008217 (Reactome)
Promotor region of interferon beta R-ALL-1008217 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
RIPK3 ProteinQ9Y572 (Uniprot-TrEMBL)
RIPK3ProteinQ9Y572 (Uniprot-TrEMBL)
RNA Polymerase III HoloenzymeComplexR-HSA-1964460 (Reactome)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Rotavirus dsRNA R-ROT-8982440 (Reactome)
STAT6 ProteinP42226 (Uniprot-TrEMBL)
STAT6ProteinP42226 (Uniprot-TrEMBL)
STING:STINGComplexR-HSA-2395989 (Reactome)
STING:STINGComplexR-HSA-3134799 (Reactome)
STING:TBK1:IRF3ComplexR-HSA-1834956 (Reactome)
STING:TBK1:STAT6ComplexR-HSA-3249399 (Reactome)
STING:TRIM32/TRIM56ComplexR-HSA-1834963 (Reactome)
STING:c-di-GMPComplexR-HSA-2395983 (Reactome)
STING:cGAMPComplexR-HSA-3244600 (Reactome)
STING:p-S172,K48polyUb-TBK1:IRF3ComplexR-HSA-3465596 (Reactome)
STING:p-S172-TBK1:IRF3ComplexR-HSA-2396004 (Reactome)
STING:p-S172-TBK1:STAT6ComplexR-HSA-3249391 (Reactome)
STING:p-S172-TBK1ComplexR-HSA-2396005 (Reactome)
TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
TBK1ProteinQ9UHD2 (Uniprot-TrEMBL)
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TMEM173 ProteinQ86WV6 (Uniprot-TrEMBL)
TMEM173ProteinQ86WV6 (Uniprot-TrEMBL)
TMPMetaboliteCHEBI:17013 (ChEBI)
TREX1 ProteinQ9NSU2 (Uniprot-TrEMBL)
TREX1 dimerComplexR-HSA-3244607 (Reactome)
TREX1:viral DNAComplexR-HSA-3244619 (Reactome)
TRIM21 ProteinP19474 (Uniprot-TrEMBL)
TRIM21ProteinP19474 (Uniprot-TrEMBL)
TRIM32 ProteinQ13049 (Uniprot-TrEMBL)
TRIM32/TRIM56ComplexR-HSA-3244609 (Reactome)
TRIM56 ProteinQ9BRZ2 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
Unmethylated CpG DNA R-ALL-3134861 (Reactome)
Unmethylated CpG DNAR-ALL-3134861 (Reactome)
VACV dsDNA R-VVI-9013755 (Reactome)
XRCC5 ProteinP13010 (Uniprot-TrEMBL)
XRCC6 ProteinP12956 (Uniprot-TrEMBL)
ZBP1 ProteinQ9H171 (Uniprot-TrEMBL)
ZBP1 ligandComplexR-NUL-8982083 (Reactome)
ZBP1ProteinQ9H171 (Uniprot-TrEMBL)
beta-catenin:IRF3:p300ComplexR-HSA-3134898 (Reactome)
c-GMP-AMP MetaboliteCHEBI:71580 (ChEBI)
c-GMP-AMPMetaboliteCHEBI:71580 (ChEBI)
c-di-AMP MetaboliteCHEBI:47037 (ChEBI)
c-di-AMP, c-di-GMPComplexR-ALL-8982080 (Reactome)
c-di-GMP MetaboliteCHEBI:49537 (ChEBI)
c-di-GMPMetaboliteCHEBI:49537 (ChEBI)
cGAS ligandsComplexR-NUL-8982071 (Reactome)
cGAS:dsDNAComplexR-HSA-3244625 (Reactome)
dCMPMetaboliteCHEBI:15918 (ChEBI)
dsDNA:IFI16ComplexR-HSA-1834947 (Reactome)
dsDNA:LRR

FLII-interacting

protein 1dimer
ComplexR-HSA-3134917 (Reactome)
dsDNA:LRRFIP1:beta-cateninComplexR-HSA-3134925 (Reactome)
dsDNA:ZBP1:RIP1:RIP3ComplexR-HSA-1810470 (Reactome)
dsDNA:ZBP1:pS-172,K48polyUb-TBK1ComplexR-HSA-3465595 (Reactome)
dsDNA:ZBP1:pS-172-TBK1ComplexR-HSA-1606333 (Reactome)
dsDNA:ZBP1:pS-172-TBK:IRF3ComplexR-HSA-1606328 (Reactome)
dsDNA:ZBP1ComplexR-HSA-1591233 (Reactome)
p-2S-IRF7:p-2S-IRF7ComplexR-HSA-450344 (Reactome)
p-4S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-4S,T404-IRF3ProteinQ14653 (Uniprot-TrEMBL)
p-S172-TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
p-S176,S180-CHUK ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S19,S23-NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
p-S407,Y641-STAT6 dimerComplexR-HSA-3249385 (Reactome)
p-S407,Y641-STAT6 dimerComplexR-HSA-3261240 (Reactome)
p-S407,Y641-STAT6 ProteinP42226 (Uniprot-TrEMBL)
p-S407,Y641-STAT6ProteinP42226 (Uniprot-TrEMBL)
p-S407-STAT6ProteinP42226 (Uniprot-TrEMBL)
p-S477,S479-IRF7 ProteinQ92985 (Uniprot-TrEMBL)
p-S552-CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
p-S552-CTNNB1ProteinP35222 (Uniprot-TrEMBL)
p-T,4S-IRF3:p-T,4S-IRF3ComplexR-HSA-166272 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3ComplexR-HSA-177675 (Reactome)
pS-172,K48polyUb-TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
viral dsRNA:TLR3:TICAM1:RIPK1ComplexR-HSA-177649 (Reactome)
viral DNA with 3' sticky endsComplexR-HIV-177535 (Reactome)
viral minus strand DNA with sticky 3' end R-HIV-177533 (Reactome)
viral plus strand DNA with sticky 3' end R-HIV-177540 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2'-deoxyadenosine 5'-monophosphateArrowR-HSA-3245943 (Reactome)
2'-deoxyguanosine 5'-monophosphateArrowR-HSA-3245943 (Reactome)
2xp-S477,S479-IRF7ArrowR-HSA-9604487 (Reactome)
5'-ppp-AU-rich dsRNAArrowR-HSA-1964482 (Reactome)
ADPArrowR-HSA-1606324 (Reactome)
ADPArrowR-HSA-1606327 (Reactome)
ADPArrowR-HSA-168140 (Reactome)
ADPArrowR-HSA-168910 (Reactome)
ADPArrowR-HSA-2396002 (Reactome)
ADPArrowR-HSA-2396007 (Reactome)
ADPArrowR-HSA-3134904 (Reactome)
ADPArrowR-HSA-3249371 (Reactome)
ADPArrowR-HSA-3249379 (Reactome)
ADPArrowR-HSA-3249390 (Reactome)
ATPR-HSA-1606324 (Reactome)
ATPR-HSA-1606327 (Reactome)
ATPR-HSA-168140 (Reactome)
ATPR-HSA-168910 (Reactome)
ATPR-HSA-2396002 (Reactome)
ATPR-HSA-2396007 (Reactome)
ATPR-HSA-3134904 (Reactome)
ATPR-HSA-3244614 (Reactome)
ATPR-HSA-3249371 (Reactome)
ATPR-HSA-3249379 (Reactome)
ATPR-HSA-3249390 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-168910 (Reactome)
CREBBP,EP300R-HSA-3134883 (Reactome)
CTNNB1R-HSA-3134901 (Reactome)
DDX41 viral ligandR-HSA-3134822 (Reactome)
DDX41:DDX41 ligandArrowR-HSA-1834939 (Reactome)
DDX41:DDX41 ligandArrowR-HSA-3134822 (Reactome)
DDX41:c-di-AMP, c-di-GMPArrowR-HSA-1834939 (Reactome)
DDX41:c-di-AMP, c-di-GMPArrowR-HSA-9013869 (Reactome)
DDX41R-HSA-3134822 (Reactome)
DDX41R-HSA-3134946 (Reactome)
DDX41R-HSA-9013869 (Reactome)
DHX36:CpG:MyD88ArrowR-HSA-9604487 (Reactome)
DHX36:CpGArrowR-HSA-3134962 (Reactome)
DHX36R-HSA-3134962 (Reactome)
DHX9/DHX36:CpG:MyD88ArrowR-HSA-3134953 (Reactome)
DHX9/DHX36:CpGR-HSA-3134953 (Reactome)
DHX9:CpG:MyD88ArrowR-HSA-9604480 (Reactome)
DHX9:CpGArrowR-HSA-3134954 (Reactome)
DHX9R-HSA-3134954 (Reactome)
DNA-PK ligandsR-HSA-3134821 (Reactome)
DNA-PK:microbial dsDNAArrowR-HSA-1834939 (Reactome)
DNA-PK:microbial dsDNAArrowR-HSA-3134821 (Reactome)
DTX4ArrowR-HSA-3249386 (Reactome)
DTX4ArrowR-HSA-8948709 (Reactome)
DTX4R-HSA-3249392 (Reactome)
DTX4R-HSA-8948703 (Reactome)
Double-stranded DNAR-HSA-3204303 (Reactome)
GTPR-HSA-3244614 (Reactome)
H2OR-HSA-3245943 (Reactome)
HCV dsDNAR-HSA-3134896 (Reactome)
IFI16 ligandsR-HSA-1834951 (Reactome)
IFI16R-HSA-1834951 (Reactome)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBArrowR-HSA-168910 (Reactome)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBmim-catalysisR-HSA-168140 (Reactome)
IRF3R-HSA-1606345 (Reactome)
IRF3R-HSA-1834939 (Reactome)
K48polyUb-DDX41:TRIM21ArrowR-HSA-3134946 (Reactome)
K63polyUb-STINGArrowR-HSA-3134804 (Reactome)
Ku70:Ku80 heterodimerR-HSA-3134821 (Reactome)
LRR FLII-interacting protein 1 dimerR-HSA-3134896 (Reactome)
MB21D1R-HSA-3244647 (Reactome)
MRE11:dsDNAArrowR-HSA-1834939 (Reactome)
MRE11:dsDNAArrowR-HSA-3204303 (Reactome)
MRE11AR-HSA-3204303 (Reactome)
MYD88R-HSA-3134953 (Reactome)
Mg2+R-HSA-3244605 (Reactome)
NFKB1(1-433), NFKB2(1-454):RELAArrowR-HSA-168140 (Reactome)
NFKB1(1-433), NFKB2(1-454):RELAR-HSA-9604480 (Reactome)
NFkB ComplexArrowR-HSA-9604480 (Reactome)
NFkB inhibitor:NFkB complexR-HSA-168140 (Reactome)
NKIRASTBarR-HSA-168140 (Reactome)
NLRC3TBarR-HSA-1834939 (Reactome)
NLRP4:DTX4:STING:p-S172-TBK1:IRF3ArrowR-HSA-3249392 (Reactome)
NLRP4:DTX4:STING:p-S172-TBK1:IRF3R-HSA-8948709 (Reactome)
NLRP4:DTX4:STING:p-S172-TBK1:IRF3TBarR-HSA-2396007 (Reactome)
NLRP4:DTX4:STING:p-S172-TBK1:IRF3mim-catalysisR-HSA-8948709 (Reactome)
NLRP4:DTX4:dsDNA:ZBP1:pS-172-TBK1ArrowR-HSA-8948703 (Reactome)
NLRP4:DTX4:dsDNA:ZBP1:pS-172-TBK1R-HSA-3249386 (Reactome)
NLRP4:DTX4:dsDNA:ZBP1:pS-172-TBK1TBarR-HSA-1606327 (Reactome)
NLRP4:DTX4:dsDNA:ZBP1:pS-172-TBK1mim-catalysisR-HSA-3249386 (Reactome)
NLRP4ArrowR-HSA-3249386 (Reactome)
NLRP4ArrowR-HSA-8948709 (Reactome)
NLRP4R-HSA-3249392 (Reactome)
NLRP4R-HSA-8948703 (Reactome)
PPiArrowR-HSA-3244614 (Reactome)
PRKDCR-HSA-3134821 (Reactome)
Phospho-NF-kappaB InhibitorArrowR-HSA-168140 (Reactome)
Pol-III ligandsR-HSA-1964482 (Reactome)
Promotor region of interferon betaR-HSA-3134883 (Reactome)
R-HSA-1591234 (Reactome) ZBP1(DAI) binds to double-stranded DNA in vitro and in vivo (Wang ZC et al 2008; Takaoka A et al 2007). N-teminus of ZBP1 contains two Z-DNA (Zalpha and Zbeta) and one B-DNA binding domains (D3 region). D3 region mediates initial binding of ZBP1 to DNA with subsequent stabilization provided by the Zalpha and Zbeta domains. All tree DNA-binding domains are required for ZBP1 full activation (Wang ZC et al 2008).

ZBP1 was reported to form multimer upon DNA binding that might facilitate innate immune responces (Wang ZC et al 2008; Ha SC et al 2008).

R-HSA-1606324 (Reactome) ZBP1 (DAI) dimer formation enables recruitment of TBK1 and IRF3 to the C-terminal region of DAI in response to cytosolic DNA in murine L929 cells. This interaction is DNA-dependent as ZBP1(DAI) mutants that lack DNA binding domains neither recruited TBK1 nor activated IRF3 (Takaoka A et al 2007). Activation of IRF-3 and possibly IRF-7 promotes IFN gene expression.
R-HSA-1606327 (Reactome) IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring Ser386 and/or Ser385- site 1; and a cluster of serine/threonine residues between Ser396 and Ser405- site 2 [Panne et al 2007]. Phosphorylated residues at site 2 (Ser396 - Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). Phosphorylation at site 1 is required for IRF3 dimerization.
R-HSA-1606345 (Reactome) ZBP1 (DAI) dimer formation enables recruitment of TBK1 and IRF3 to the C-terminal region of DAI in response to cytosolic DNA in murine L929 cells. This interaction is DNA-dependent as ZBP1(DAI) mutants that lack DNA binding domains neither recruited TBK1 nor activated IRF3 (Takaoka A et al 2007). Activation of IRF-3 and possibly IRF-7 promotes IFN gene expression.
R-HSA-168140 (Reactome) In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits.

A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB.

R-HSA-168910 (Reactome) RIP1 polyubiquitination was induced upon TNF- or poly(I-C) treatment of the macrophage cell line RAW264.7 and the U373 astrocytoma line (Cusson-Hermance et al 2005). These workers have suggested that RIP1 may use similar mechanisms to induce NF-kB in the TNFR1- and Trif-dependent TLR pathways.

RIP1 modification with Lys-63 polyubiquitin chains was shown to be essential for TNF-induced activation of NF-kB (Ea et al. 2006). It is thought that TRAF family members mediate this Lys63-linked ubiquitination of RIP1 (Wertz et al. 2004, Tada et al 2001, Vallabhapurapu and Karin 2009), which may facilitate recruitment of the TAK1 complex and thus activation of NF-kB. Binding of NEMO to Lys63-linked polyubiquitinated RIP1 is also required in the signaling cascade from the activated receptor to the IKK-mediated NF-kB activation (Wu et al. 2006).

R-HSA-1810457 (Reactome) Two RIP homotypic interaction motifs (RHIM) were identified in the DAI protein sequence. These two domains were shown to be essential for DAI-induced NFkB activation in human embryonic kidney 293T (HEK293T) cells. DAI forms a complex with two RHIM-containing kinases - RIP1 and RIP3 (Kaiser WJ et al 2008, Rebsamen M et al 2009). Recruitment of RIP3 to DAI was reported to induce RIP3 autophosphorylation. Furthermore, knockdown of RIP1 or RIP3 affected DAI-induced NFkB signals in murine L929 fibroblast and human HEK293T cells (Kaiser WJ et al 2008, Rebsamen M et al 2009).
R-HSA-1834939 (Reactome) In dsDNA-stimulated human and mouse cells TBK1 has been shown to move to cytoplasmic punctate structures, where it associates with STING to induce IRF3 activation (Ishikawa et al. 2009, Saitoh et al. 2009, Sun et al. 2009, Tanaka & Chen 2012). Co-immunoprecipitation assays in HEK 293T cells expressing HA-tagged STING and Flag-tagged TBK1 showed that TBK1 directly interacts with STING. Moreover, glutathione S-transferase (GST) pull-down assays showed that recruitment of TBK1 by STING was enhanced upon c-di-GMP binding (Ouyang et al. 2012).

STING was reported to mediate TBK1-dependent activation of transcription factor IRF3 (Zhong B et al. 2008, Tanaka and Chen 2012). Both TBK1 and IRF3 can directly interact with STING through its C-terminal region (Tanaka & Chen 2012). A construct of human STING containing only 39 amino acid residues of its C-terminus (341 to 379) was sufficient to activate IRF3 in cytosolic extracts of HeLa cells. Further mutagenesis studies showed, that two residues, Ser366 and Leu374, within the C-terminal tail of STING were required for IRF3 binding and phosphorylation, but were dispensable for TBK1 binding and activation (Tanaka & Chen 2012). Thus, STING is thought to function as a scaffold to recruit cytosolic TBK1 and IRF3, which results in TBK1-dependent phosphorylation of IRF3. Importantly, though both STING monomers and dimers can bind TBK1, only STING dimers activates Type I IFN (Ouyang et al. 2012). The nucleotide binding domain and leucine-rich repeat-containing (NLR) protein NLRC3 interacts with STING and TBK1, reducing STING-TBK1 association and reduces the trafficking of STING to the perinuclear region, leading to decreased activation of innate immune cytokines (Zhang et al. 2014).

R-HSA-1834951 (Reactome) Interferon (IFN)-inducible IFI16 protein was shown to be critical for type I IFN and pro inflammatory responses in viral DNA-stimulated human and mouse cells [Unterholzner L et al 2010; Kerur N et al 2011; Li T et al 2012]. Despite being predominantly nuclear, IFI16 can sense pathogenic DNA in both the cytoplasm and the nucleus. Cytosolic IFI16 can directly bind viral dsDNA motifs via its HIN200 domains in human monocytic leukemia THP-1 cell extracts. IFI16-mediated response to cytosolic DNA was reported to induce type I IFN production in a STING-TBK1- and IRF3 dependent manner [Unterholzner L et al 2010].

Nuclear IFI16 can detect kaposi sarcoma-associated herpesvirus (KSHV) DNA which results in IL-1beta maturation and caspase-1 inflammasome activation in human cells [Kerur N et al 2011]. Importantly, acetylation of the nuclear localization signal (NLS) of IFI16 in lymphocytes and macrophages leads to cytosolic accumulation of IFI16 and is important for its type I IFN stimulation ability in cytoplasm [Li T et al 2012].

R-HSA-1964482 (Reactome) RNA polymerase III (POL III) was reported to sense and transcribe cytosolic AT-rich dsDNA into 5'-triphosphate poly(A-U) RNA in human and mouse cells. This dsRNA ligand in turn activated retinoic acid-inducible gene I (RIG-I) leading to production of type I interferon and activation of the transcription factor NF-kappaB (Chiu YH et al. 2009, Ablasser A et al. 2009). Knockdown of POL III expression by siRNA or inhibition of its enzymatic activity by specific chemical inhibitor ML-60218 prevented IFN beta induction in HEK293 cells stimulated with DNA viruses or poly(dA-dT) (Chiu YH et al. 2009, Ablasser A et al. 2009). Moreover, Pol-III inhibition blocked interferon induction by intracellular Legionella pneumophila bacteria [Chiu YH et al 2009].

This project represents cytosolic RNA polymerase III as a complex comprising 17 subunits, although the precise biochemical composition of the cytosolic holoenzyme complex which specifically recognizes AT-rich DNA is not yet known.

R-HSA-1964496 (Reactome) Tripartite motif (TRIM) family member TRIM56 was shown to interact with STING upon DNA stimulation promoting lysine 63-linked ubiquitination of STING and type I IFN induction (Tsuchida T et al. 2010). Another member of the family TRIM32 has also been implicated in K63-linked ubiquitination of STING (Zhang J et al. 2012).
R-HSA-2032396 (Reactome) IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm.
R-HSA-2395992 (Reactome) IRF3 phosphorylation promotes IRF3 dimerization and nuclear translocation, which results in the production of type I interferons (IFNs).
R-HSA-2396002 (Reactome) TBK1 activity is regulated by phosphorylation of Ser-172 within the kinase activation loop [Kishore N et al 2002]. TBK1 phosphorylation is thought to be an autoactivation event. Biochemical analysis demonstrated that the kinase domain alone was sufficient to fully autoactivate TBK1 and was capable of phosphorylating both macromolecular and peptide substrates [Ma X et al 2012]. Furthermore, TBK1 can autophosphorylate at Ser-172 and autoactivate when overexpressed in HEK293 cells. Additionally, in co-transfection experiments wild type TBK1 associated with and phosphorylated the catalytically inactive mutant TBK1-(K38A) at Ser-172 [Clark K et al 2009]. Studies of the crystal structure of TBK1 in complex with a potent small-molecule inhibitor BX795 revealed that Ser-172 from one protomer is located in close proximity to the active site of the neighboring protomer, providing a snapshot of a potential transautoactivation reaction intermediate [Ma X et al 2012]. However, involvement of a distinct upstream activating kinase in the TBK1 phosphorylation should not be ruled out [Clark K et al 2009].
R-HSA-2396007 (Reactome) IRF3 is activated through a two-step phosphorylation in the C-terminal domain mediated by TBK1 and/or IKKi, requiring Ser386 and/or Ser385- site 1; and a cluster of serine/threonine residues between Ser396 and Ser405- site 2 [Panne et al 2007]. Phosphorylated residues at site 2 (Ser396 - Ser405) alleviate autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitate phosphorylation at site 1 (Ser385 or Ser386). Phosphorylation at site 1 is required for IRF3 dimerization.
R-HSA-2396009 (Reactome) Cyclic di-GMP (c-di-GMP) and cyclic-di-AMP (c-di-AMP) are ubiquitous secondary messengers secreted by bacteria, but not by eukarya. UV cross-linking experiment with radiolabeled c-di-GMP in lysates of human embryonic kidney 293T (HEK293T) cells expressing mouse Sting showed that STING recognizes and directly binds to c-di-GMP [Burdette DL et al 2011]. STING was reported to contain multiple trans-membrane regions at its N-terminus while its C-terminal domain (CTD) is cytosolic. Mutational analysis showed that the CTD is responsible for the binding to c-di-GMP and this binding enhances the recruitment of TBK1 by STING [Ouyang S et al 2012]. Furthermore, a C-terminal tail (CTT) within the CTD interacts with and activates TBK1 and IRF3 [Tanaka Y and Chen ZJ 2012]. Impotantly, Sting is required for both c-di-GMP and c-di-AMP induced type I IFN production in mouse cultured macrophages infected with intracellular pathogens in vitro [Jin L et al 2011; Sauer JD et al 2011]. Low levels of STING protein expressed in human embryonic kidney (HEK293T) cells were sufficient to reconstitute the responsiveness of the cells to both c-di-GMP and c-di-AMP [Burdette DL et al 2011]. However, structural studies of STING revealed, that STING prefers c-di-GMP over c-di-AMP [Ouyang S et al 2012].

Several studies have demonstrated that human STING functions as a dimer and STING dimerization was essential for the induction of IFN response [Sun W et al 2009; Burdette DL et al 2011; Jin L et al 2011; Ouyang S et al 2012]. Mouse Sting/Myps has been also reported to exist as a dimer constitutively [Jin L et al 2008]. Moreover, STING can function as a ROS sensor, which forms a disulfide-linked homodimer under conditions of oxidative stress in HEK293T cells [Jin L et al 2010]. Structure analysis of the C-terminal domain in complex with c-di-GMP revealed that two STING molecules associate with one molecule of c-di-GMP [Ouyang S et al 2012; Yin Q et al 2012; Scu C et al 2012]. The STING dimer is thought to have a V-shaped structure, and the c-di-GMP binding site is located at the bottom of the V of the dimer interface [Scu C et al 2012]. Isothermal titration calorimetry (ITC) experiments confirmed the stoichiometry of STING to c-di-GMP as 2:1 with a binding dissociation constant (Kd) of ~2.4 microM [Yin Q et al 2012; Scu C et al 2012]. The data are consistent with a previous measurement of mouse STING CTD binding affinity to c-di-GMP using equilibrium dialysis [Burdette DL et al 2011]. Although STING is considered as a direct sensor of bacterial c-di-GMP, it is noteworthy, that the binding affinity of c-di-GMP to mammalian STING is much weaker than to bacterial sensors. For example, E.coli protein YcgR binds to c-di-GMP with a Kd of ~0.84 microM [Ryjenkov DA et al 2006]. Also taking into account that, the normal concentration of c-di-GMP in bacteria varies from 0.1~10 microM, it remains to be determined whether STING binds to c-di-GMP under physiological conditions.

R-HSA-3134800 (Reactome) Several studies have demonstrated that human STING functions as a dimer and STING dimerization was essential for the induction of IFN response (Sun W et al. 2009; Burdette DL et al. 2011; Jin L et al. 2011; Ouyang S et al. 2012). Mouse Sting/Myps has been also reported to exist as a dimer constitutively [Jin L et al 2008]. Moreover, STING can function as a ROS sensor, which forms a disulfide-linked homodimer under conditions of oxidative stress in HEK293T cells [Jin L et al 2010]. Structural studies revealed that the strictly conserved cytosolic aa 153-173 region of STING participates in dimerization via hydrophobic interactions (Ouyang S et al. 2012).

STING was shown to undergo K63-linked ubiquitination, which may facilitate its dimerization (Tsuchid T et al. 2010; Zhang J et al. 2012)

R-HSA-3134804 (Reactome) E3 ubiquitin-protein ligase TRIM32 and TRIM56 were shown to enhance type I IFN induction and cellular antiviral response by promoting K63-linked ubiquitination of STING.
R-HSA-3134821 (Reactome) DNA-dependent serine/threonine protein kinase DNA-PK is a DNA damage sensor, which is composed of a large catalytic subunit DNA-PKcs and a heterodimer of Ku70 & Ku80 subunits. DNA-PK was found both in the nucleus and in the cytosol (Lucero H et al. 2003). While in the nucleus DNA-PK is critical for the repair of double-stranded DNA breaks during the lymphocyte development, in the cytosol it can also bind DNA fragments to transmit stress signals (Dip R & Naegeli H 2005; Yotsumoto S et al. 2008; Dragoi AM et al. 2004; Ferguson BJ et al. 2012).

This Reactome event presents DNA-PK as a holoenzyme, however it remains unclear whether all DNA-PK subunits are critical for exogenous DNA recognition, whether they function as a DNA-PK complex or each subunit acts independently in certain circumstances (Zhang X et al. 2011; Ferguson BJ et al. 2012).

Studies involving different human and mouse cell lines yielded variable results regarding to DNA-PK signaling functions. The catalytic subunit DNA-PKcs has been shown to associate with Akt upon CpG-OND-stimulation triggering transient nuclear translocation of Akt in mouse bone marrow-derived macrophages (BMDMs)(Dragoi AM et al. 2004). DNA-PKcs has been also reported to induce ERK activation and production of anti-inflammatory cytokine IL-10 in CpG-ODN-stimulated mouse monocyte/macrophage cell line RAW264.7, while production of pro-inflammatory cytokine IL-12 was negatively regulated (Yotsumoto S et al. 2008). In addition, endosomal translocation of CpG-ODN was found to regulate DNA-PKcs-mediated responses to CpG-OND (Yotsumoto S et al. 2008; Hazeki K et al. 2011). Moreover, DNA-PK subunits have been implicated in IFN regulatory factor (IRF)-dependent innate immune responses. Ku-70 was shown to induce production of type III IFN (IFN -lamda 1) in human embryonic kidney HEK293 cells transfected with DNA. The Ku70-mediated IFN-lamda 1 activation required a longer size of DNA (>500 bp DNA) (Zhang X et al. 2011). Whether DNA-PK mediates activation of IFN-beta production is debatable. Ku70- or DNA-PKcs-deficient mouse bone marrow-derived macrophages cells mounted an identical IFN-beta response when compared to their wild-type controls (Stetson DB & Medzhitov R 2006). However, the other group demonstrated that DNA-PK induced IRF3-dependent production of IFN-beta in DNA-stimulated mouse embryonic fibroblast(MEF) and human HEK293 cells (Ferguson BJ et al. 2012). Thus, the molecular mechanism behind DNA-PK activation by cytosolic DNA remains to be clarified.

It's interesting to note that in the nucleus DNA-PK may regulate IRF3 transcriptional activity in response to viral infection. DNA-PK was found to bind and phosphorylate IRF-3 at Thr-135 in Sendai virus (SV)-treated human endometrial adenocarcinoma HEC1B cells. DNA-PK-dependent phosphorylation at Thr-135 is thought to retain transcriptionally active IRF-3 in the nucleus (Karpova AY et al. 2002).

R-HSA-3134822 (Reactome) The helicase DDX41 was shown to sense exogenous DNA in human and mouse cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 was also reported to sense and interact with bacterial secondary messengers cyclic di-GMP or cyclic di-AMP (Parvatiyar K et al. 2012). Mutagenesis analysis with DDX41 deletion constructs revealed that the central DEAD-box domain of DDX41 mediated the binding with DNA (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Knockdown of DDX41 or STING in human cells (THP-1 and PBMC cells) and mouse dendritic cells significantly reduced the cytokine production in response to pathogen-derived DNA or poly(dG:dC) (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 localized together with STING in the cytoplasm when both DDX41 and STING were co-expressed in HEK293T cells (Zhang Z et al. 2011). Mouse Ddx41 was found to bind Sting and Tbk1 in both resting and poly(dA:dT)-stimulated mouse splenic myeloid dendritic cell (D2SC mDCs) (Zhang Z et al. 2011). Ddx41-Sting interaction was also observed in c-di-GMP- or c-di-AMP-treated D2SC cells (Parvatiyar K et al. 2012). Moreover, knockdown of Ddx41 or Sting inhibited phosphorylation of Tbk1, Irf3, p65 subunit of NF-kappaB and other signal transducers in DNA-stimulated mouse bone marrow-derived (BMDCs) and D2SC cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Collectively, these data suggest that DNA triggers DDX41 downstream signaling to type I interferon in a STING-dependent manner.

The E3 ubiquitin ligase TRIM21 was reported to promote the K48-linked ubiquitination and degradation of DDX41 leading to downregulation of the type I interferon production in mouse mDC and human monocytes THP-1 (Zhang Z et al. 2013).

R-HSA-3134883 (Reactome) Beta-catenin increases IFN-beta expression by binding to the C-terminal domain of the transcription factor IRF3 and recruiting the acetyltransferase p300 to the IFN-beta enhanceosome via IRF3.
R-HSA-3134896 (Reactome) LRRFIP1 can recognize both AT-rich B-form dsDNA and GC-rich Z-form dsDNA (Yang P et al. 2010). Induction of IFN-beta by LRRFIP1 was enhanced with the presence of hepatitis C virus (Liu Y et al. 2015). Overexpression of LRRFIP1 in hepatocyte derived cellular carcinoma cell lines (Huh7 and Huh7.5.1) inhibited HCV replication. However, HCV infection did not regulate intracellular expression of LRRFIP1 (Liu Y et al. 2015). In addition, the C-terminus of LRRFIP1 has been described as having nucleic acid-binding activity, including the transactivating response region (TAR) hairpin of HIV (Liu YT & Yin HL 1998; Choe N et al. 2013). Moreover, LRRFIP1 induced type I IFNs in 3T3 cells in the presence of influenza virus and contributed to the production of IFN-beta in mouse macrophages induced by VSV (vesicular stomatitis virus) and Listeria monocytogenes (Bagashev A et al. 2010; Yang P et al. 2010).

LRRFIP1 contains three domains, an N-terminal helical region of unknown function, a central coiled coil (CC) domain that interacts with protein flightless I homolog (FLII), and a C-terminal DNA binding or nucleic acid recognition domain (DBD). The structural and biophysical studies revealed that the CC-domain of LRRFIP1 forms stable homodimer in solution while the CC-DBD construct was found to be an oligomer suggesting that the full length LRRFIP1 may also form dimers or larger oligomers upon DNA binding (Nguyen JB and Modis Y 2012).

R-HSA-3134901 (Reactome) The cytosolic protein beta-catenin is known as a transcriptional cofactor in Wnt signaling pathway. Beta-catenin has been also implicated in LRRFIP1-mediated induction of type I IFN. Beta-catenin was shown to bind Lrrfip1 in L. monocytogenes-infected mouse macrophages but not in resting macrophages (Yang P et al 2010). The interaction of beta-catenin and LRRFIP1 was also reported for human proteins when they were co-expressed in human embryonic kidney 293T (HEK293T) cells followed by co-immunoprecipitation assay. The co-immunoprecipitation results were consistent with the GST-pulldown data (Lee YH and Stallcup MR 2006).
R-HSA-3134904 (Reactome) Beta-catenin undergoes phosphorylation at Ser552 in a Lrrfip1-dependent manner in pathogen-infected mouse macrophages (Yang P et al. 2010). Studies on human cells showed that the protein kinase Akt can phosphorylate beta-catenin at Ser552 upon treatment with various stimuli such as epidermal growth factor (EGF) or hepatitis C virus (HCV). However, it remains to be determined which kinase is involved in up-regulation of beta-catenin downstream of LRRFIP1 (Fang D et al. 2007; Bose SK et al. 2012). Phosphorylated beta-catenin translocates to the nucleus.
R-HSA-3134914 (Reactome) Phosphorylated beta-catenin migrates to the nucleus where it functions as a coactivator of IRF3-dependent transcription (Yang P et al. 2010).

Beta-catenin transport to the nucleus is thought to occur in a NLS (nuclear localization signal)- and importin-independent manner through direct interaction with the nuclear pore complex (NPC) components. This has been shown to be the case for Wnt-signaling in mammalian cells (Yokoya F et al. 1999; Koike M et al. 2004; Sharma M et al. 2012)

R-HSA-3134946 (Reactome) TRIM21 (Ro52/SSA1) is a member of the TRIM (Tripartite Motif) family of E3 ligases. E3 activity of TRIM21 was found to be a RING domain-dependent and required E2-conjugating enzymes UBE2D1/2/3/4 and UBE2E1/2 (Espinosa A et al. 2011).

TRIM21 can form a complex with DDX41 leading to the K48-linked ubiquitination and degradation of DDX41 (Zhang Z et al. 2013).

R-HSA-3134953 (Reactome) Both DHX36 and DHX9 were found to interact with MyD88 when co-expressed in human embryonic kidney 293T cells. Moreover, the HA2 and DUF domains of DHX were critical for interaction with the TIR domain of MyD88 [Kim T et al 2010].

DHX9 or DHX36 knockdown by siRNA inhibited cytokine release in human GEN2.2 cell line (leukemic pDC cells) in response to CpG-ODN or to HSV but not to RNA viruses. Furthermore, knockdown of DHX36 diminished the nuclear localization of IRF7 in CpG-A-stimulated cells, while knockdown of DHX9 inhibited nuclear localization of NF-kappaB p50 in response to CpG-B. Thus, DHX36 and DHX9 are thought to trigger MyD88-dependent IRF7 and NF-kappaB activation respectively [Kim T et al 2010].

R-HSA-3134954 (Reactome) DHX9 binds CpG-B in human plasmacytoid dendritic cells (pDC). The DUF domain of DHX9 was shown to be essential for binding CpG-B [Kim T et al 2010].
R-HSA-3134962 (Reactome) DHX36 senses CpG-A in cytosol of human plasmacytoid dendritic cells. DEAH domain of DHX36 was found to be essential for binding CpG-A [Kim T et al 2010].
R-HSA-3204303 (Reactome) DNA damage sensor, meiotic recombination 11 homolog A (MRE11) has been shown to function as a cytosolic sensor of dsDNA. The observations that MRE11 mediates recognition of dsDNA rather than pathogens suggest that the biological significance of MRE11-mediated intracellular DNA recognition is to respond to damaged host cells, rather than defense against foreign pathogens (Kondo T et al. 2013). Cells with a mutation of MRE11 gene derived from a patient with ataxia-telangiectasia-like disorder, and cells in which Mre11 was knocked down, had defects in dsDNA-induced type I IFN production (Kondo T et al. 2013).
R-HSA-3244605 (Reactome) TREX1 was shown to bind and degrade the HIV DNA fragments, which were generated during reverse transcription in HIV-infected human cells (Yan N et al. 2010). Other studies showed that TREX1 may regulate host responses to infection with several different types of RNA viruses (Hasan M et al. 2012). TREX1 is thought to clear viral derived DNA from the cytoplasm and thereby inhibit the activation of cytosolic DNA sensors (Yan N et al. 2010; Hasan M et al. 2012).

Structural studies of the human and mouse TREX proteins revealed the dimeric nature of the TREX family exonucleases (Brucet M et al. 2007; de Silva U et al. 2007, 2009; Perrino FW et al. 2005; Bailey SL et al 2012). Besides, the stable TREX1 dimer was purified from bacterial cells expressing affinity-tagged human TREX1 proteins (Orebaugh CD et al. 2011).Comparative structural analysis of wild type (wt) and natural mutant variants of TREX1 in complex with ssDNA provided some insights into mechanism of the TREX1 exonuclease activity (Bailey SL et al 2012). The reaction begins with the binding of metal ions and DNA substrate in the enzyme active site, which results in the transition of catalytic histidine residue H195 from a disordered to an ordered state. The distance between two divalent metal ions is also essential for catalytic activity. The authors proposed a mechanism where the two protomers in TREX1 dimer alternate back and forth between active and resting states as they degrade substrate. The activity status is mediated by the dual conformation of H195, which is coordinated with the shift of the metal ion from 3.1 A when H195 is out of the active site (resting) to 3.6 A when H195 moves into the active site (active) (Bailey SL et al 2012). In addition, the structures of the TREX1 mutant proteins (dominant D200H, D200N and D18N homodimer mutants derived from AGS and FCL patients, as well as the recessive V201D mutant) provided insight into the dysfunction relating to human diseases (Bailey SL et al. 2012). The comparative analysis of the exonuclease activity of the dominant mutant TREX1 proteins (homo- and heterodimers generated from wt- and mutant TREX1 monomers) are in agreement with findings of Bailey et al.(Lehtinen DA et al. 2008; Fye JM et al. 2011; Bailey SL et al. 2012).

R-HSA-3244614 (Reactome) Cyclic dinucleotides (such as c-di-GMP and c-di-AMP) are signaling molecules produced by bacteria. In host cells they are recognized by DNA sensors such as DDX41 and STING to trigger IFN production in a STING-dependent manner (Burdette DL et al. 2011; Yin Q et al. 2012; Parvatiyar K et al. 2012). Cyclic adenosine monophosphate-guanosine monophosphate (cyclic GMP-AMP, cGAMP) has been also implicated in stimulating host responses via STING (Wu J et al. 2013). Chemically synthesized cGAMP was shown to induce IFN-beta production in mouse fibrosarcoma cell line L929 with much higher potency than c-di-GMP and c-di-AMP. Most importantly, cGAMP was identified as the first cyclic di-nucleotide produced by mammalian cells (Wu J et al. 2013). DNA transfection or DNA virus infection of human and mouse cells triggered production of the endogenous second messenger cGAMP, which in turn interacted with STING to activate dimerization of IRF3 and induction of IFN beta (Wu J et al. 2013). cGAMP synthase (cGAS) was reported to catalyze the cGAMP production in the presence of DNA (Sun L et al. 2013). The structural study showed that cGAMP generated by cGAS contains G(2',5')pA and A(3',5')pG phosphodiester linkages, which is distinct from bacterial 3',5' cyclic dinucleotides (Gao P et al. 2013).
R-HSA-3244643 (Reactome) Direct binding assays with radiolabeled substrate showed that the association of STING protein (residues 139-379) with [32P]-cGAMP was inhibited in the presence of competing cold cGAMP, c-di-GMP or c-di-AMP, suggesting that the cGAMP binding sites on STING might overlap with those that interact with c-di-GMP and c-di-AMP (Wu J et al.2013). Indeed, mutations of several residues that were shown to participate in the binding of STING to c-di-GMP, including S161Y, Y240S and N242A, also impaired the binding of STING to cGAMP (Yin Q et al. 2012; Wu J et al.2013). Structural study revealed that cGAMP generated by cGAS contains G(2',5')pA and A(3',5')pG phosphodiester linkages, which is distinct from bacterial 3',5' cyclic dinucleotides (Gao P et al. 2013).
R-HSA-3244647 (Reactome) Cyclic GMP-AMP (cGAMP) synthase (cGAS) was identified as a cytosolic DNA sensor, which induced STING-mediated induction of type I interferon (Sun L et al. 2013). Knockdown of cGAS inhibited IRF3 activation and IFN-beta production in human acute monocytic leukemia cell line (THP1) in response to DNA transfection or DNA virus infection. Affinity-purified human or mouse cGAS proteins from transfected human embryonic kidney HEK293T cells were able to catalyze the production of cGAMP in vitro, which stimulated IRF3 dimerization in mouse Raw264.7 cells (mouse Abelson murine leukemia virus-induced tumor cell line). The catalytic activity of cGAS was shown to depend on the presence of DNA (Sun L et al. 2013). Sun L et al. suggested that sGAS acts as a cytosolic DNA sensor, which triggers type I interferon induction by producing the second messenger cGAMP in mammalian cells.
R-HSA-3245943 (Reactome) TREX1 digests unpaired nucleotides on ssDNA and dsDNA ends through a 3' to 5' exonuclease activity (Perrino FW et al. 1994; de Silva U et al. 2007; Lehtinen DA et al. 2008; Fye JM et al 2011). Upon viral infection the TREX1-deficient human and mouse cells were found to be more resistant to different types of RNA viruses, suggesting that TREX1 activity may inhibit the host innate immune responses by clearing viral DNA generated during reverse transcription (Yan N et al. 2010; Hasan M et al. 2012).
R-HSA-3249370 (Reactome) Following tyrosine phosphorylation and dimerization STAT6 translocates to the nucleus to initiate the transcription. Virus-induced STAT6 was shown to up-regulate expression of the specific gene set (Chen H et al. 2011). Among the targets are chemokines CCL2, CCL20, and CCL26, which attract cells of immune system to fight the infection.
R-HSA-3249371 (Reactome) Upon viral infection STAT6 undergoes Ser407 phosphorylation, which was shown to depend on the TBK1 kinase activity, but not on the kinase JAK, which phosphorylates STAT6 on Tyr641 in IL4-mediated signaling (Chen H et al. 2011).
R-HSA-3249372 (Reactome) Phosphorylation of STAT6 results in the homodimerization and nucleus translocation of STAT6 where it binds to the target sites to initiate transcription.
R-HSA-3249378 (Reactome) Endogenous STAT6 was found to co-fractionate with STING from the lysates of Herpes simplex virus 1 (HSV-1) - infected HeLa cells. Similar results were obtained from Sendai virus (SeV)-infected HeLa cells, where STAT6 redistributed to the perinuclear region to co-localizes with STING upon infection. Co-immunoprecipitation assays confirmed STAT6-STING interaction in human embryonic kidney HEK293 cells. The DNA-binding domain (DBD) of STAT6 and C terminus (aa 317-379) of STING were essential for this interaction. The TBK1 kinase activity was required for virus-induced STAT6 phosphorylation, however the direct interaction between STAT6 and TBK1 is not yet reported (Chen H et al. 2011). Co-immunoprecipitation assays in HEK293T cells expressing HA-tagged STING and Flag-tagged TBK1 showed that TBK directly interacts with STING (Ouyang S et al. 2012).
R-HSA-3249379 (Reactome) TBK1 phosphorylates STAT6 on Ser407, which in turn activates another unidentified tyrosine kinase to phosphorylate STAT6 on Tyr641. Mutant constructs with Tyr641 replaced by Phe totally abolished STAT6 activity in response to virus or IL-4/IL-13 (Chen H et al. 2011).
R-HSA-3249386 (Reactome) NLRP4 regulate the host immune responses by recruiting E3 ubiquitin-protein ligase DTX4 to the kinase TBK1. DTX4 promotes K48-linked ubiquitination of TBK1 resulting in the degradation of TBK1 and downregulation of IFN signaling (Cui J et al. 2012).
R-HSA-3249390 (Reactome) Here we show that the activation of TBK1 occurs via an autophosphorylation event, although there is no direct evidence for TBK1 phosphorylation in STAT6-mediated signaling.
R-HSA-3249392 (Reactome) NLRP4 (or NACHT, LRR and PYD domains-containing protein 4) and E3 ubiquitin-protein ligase DTX4 were reported to regulate the activation of type I interferon induced by double-stranded RNA or DNA (Cui J et al. 2012). Co-transfection with various combinations of full-length and truncated NLRP4 and DTX4 proteins in human embryonic kidney HEK293T cells, followed by IFN-signaling reporter assays and immunoassays showed that Nod domain of NLRP4 regulated TBK1 activity by recruiting DTX4 through the RING domain to the kinase domain of TBK1. The E3-ligase activity of DTX4 promoted K48-linked ubiquitination of TBK1 targeting it to the proteosomal degradation.The NLRP4 and DTX4 knockdown by siRNA in peripheral blood mononuclear cells (PBMCs) and THP-1 cells resulted in higher type I interferon production following stimulation with vesicular stomatitis virus (VSV), Sendai virus, and transfected Poly(dA:dT), which may engage various cytosolic receptors to activate IFN regulatory factor 3 (IRF3) downstream of TBK1 (Cui J et al. 2012).
R-HSA-8948703 (Reactome) NLRP4 (or NACHT, LRR and PYD domains-containing protein 4) and E3 ubiquitin-protein ligase DTX4 were reported to regulate the activation of type I interferon induced by double-stranded RNA or DNA (Cui J et al. 2012). Co-transfection with various combinations of full-length and truncated NLRP4 and DTX4 proteins in human embryonic kidney HEK293T cells, followed by IFN-signaling reporter assays and immunoassays showed that Nod domain of NLRP4 regulated TBK1 activity by recruiting DTX4 through the RING domain to the kinase domain of TBK1. The E3-ligase activity of DTX4 promoted K48-linked ubiquitination of TBK1 targeting it to the proteosomal degradation.The NLRP4 and DTX4 knockdown by siRNA in peripheral blood mononuclear cells (PBMCs) and THP-1 cells resulted in higher type I interferon production following stimulation with vesicular stomatitis virus (VSV), Sendai virus, and transfected Poly(dA:dT), which may engage various cytosolic receptors to activate IFN regulatory factor 3 (IRF3) downstream of TBK1 (Cui J et al. 2012).
R-HSA-8948709 (Reactome) NLRP4 regulate the host immune responses by recruiting E3 ubiquitin-protein ligase DTX4 to the kinase TBK1. DTX4 promotes K48-linked ubiquitination of TBK1 resulting in the degradation of TBK1 and downregulation of IFN signaling (Cui J et al. 2012).
R-HSA-9013869 (Reactome) DEAD-Box Helicase 41 (DDX41) is the helicase that senses exogenous DNA in human and mouse cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 was also reported to sense and interact with bacterial secondary messengers cyclic di-GMP or cyclic di-AMP (Parvatiyar K et al. 2012). Upon ligand recognition DDX41 interacts with STING to activate TBK1/IRF3 leading to type 1 IFN production (Zhang Z et al. 2011; Lee KG et al. 2015). Mutagenesis analysis with DDX41 deletion constructs revealed that the central DEAD-box domain of DDX41 mediated the binding with DNA (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Knockdown of DDX41 or STING in human cells (THP-1 and PBMC cells) and mouse dendritic cells significantly reduced the cytokine production in response to pathogen-derived DNA or poly(dG:dC) (Zhang Z et al. 2011, Parvatiyar K et al. 2012). DDX41 localized together with STING in the cytoplasm when both DDX41 and STING were co-expressed in HEK293T cells (Zhang Z et al. 2011). Mouse Ddx41 was found to bind Sting and Tbk1 in both resting and poly(dA:dT)-stimulated mouse splenic myeloid dendritic cell (D2SC mDCs) (Zhang Z et al. 2011). Tyr364 and Tyr414 of DDX41 were found to be critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identified Tyr414 as the BTK phosphorylation site (Lee KG et al. 2015). Ddx41-Sting interaction was also observed in c-di-GMP- or c-di-AMP-treated D2SC cells (Parvatiyar K et al. 2012). Moreover, knockdown of Ddx41 or Sting inhibited phosphorylation of Tbk1, Irf3, p65 subunit of NF-kappaB and other signal transducers in DNA-stimulated mouse bone marrow-derived (BMDCs) and D2SC cells (Zhang Z et al. 2011, Parvatiyar K et al. 2012). Collectively, these data suggest that DNA triggers DDX41 downstream signaling to type I interferon in a STING-dependent manner.

The E3 ubiquitin ligase TRIM21 was reported to promote the K48-linked ubiquitination and degradation of DDX41 leading to downregulation of the type I interferon production in mouse mDC and human monocytes THP-1 (Zhang Z et al. 2013).

R-HSA-9604480 (Reactome) NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NFkappa-B2), All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefore, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.

DExH/D-box helicase (DHX9)-mediated sensing of CpG-B trigger downstream signaling to NF-κappa B. Knockdown of DHX9 expression by RNA interference in the CpG-B-treated human plasmacytoid dendritic cell line Gen2.2 inhibited nuclear localization of p50 (NF-kappa-B1) subunit of NF-κappa B complex (Kim T et al. 2010).

DNA-dependent activator of IRFs/Z-DNA binding protein 1 (ZBP1 or DAI) recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-kappaB (Rebsamen M et al. 2009).

R-HSA-9604487 (Reactome) p-IRF7 dimers are then transported into the nucleus and assemble with the coactivator CBP/p300 to activate transcription of type I interferons and other target genes.

DExH/D-box helicase 36 (DHX36)-mediated sensing of CpG-A trigger downstream signaling to activation of interferon regulatory transcription factor 7 (IRF7). Knockdown of DHX36 expression by RNA interference in the CpG-A-treated human plasmacytoid dendritic cell line Gen2.2 inhibited nuclear localization of IRF7 (Kim T et al. 2010).

RIPK1R-HSA-1810457 (Reactome)
RIPK3R-HSA-1810457 (Reactome)
RNA Polymerase III Holoenzymemim-catalysisR-HSA-1964482 (Reactome)
STAT6R-HSA-3249378 (Reactome)
STING:STINGArrowR-HSA-3134800 (Reactome)
STING:STINGR-HSA-1834939 (Reactome)
STING:STINGR-HSA-2396009 (Reactome)
STING:STINGR-HSA-3244643 (Reactome)
STING:STINGR-HSA-3249378 (Reactome)
STING:TBK1:IRF3ArrowR-HSA-1834939 (Reactome)
STING:TBK1:IRF3R-HSA-2396002 (Reactome)
STING:TBK1:STAT6ArrowR-HSA-3249378 (Reactome)
STING:TBK1:STAT6R-HSA-3249390 (Reactome)
STING:TRIM32/TRIM56ArrowR-HSA-1964496 (Reactome)
STING:TRIM32/TRIM56R-HSA-3134804 (Reactome)
STING:TRIM32/TRIM56mim-catalysisR-HSA-3134804 (Reactome)
STING:c-di-GMPArrowR-HSA-2396009 (Reactome)
STING:cGAMPArrowR-HSA-3244643 (Reactome)
STING:p-S172,K48polyUb-TBK1:IRF3ArrowR-HSA-8948709 (Reactome)
STING:p-S172-TBK1:IRF3ArrowR-HSA-2396002 (Reactome)
STING:p-S172-TBK1:IRF3R-HSA-2396007 (Reactome)
STING:p-S172-TBK1:IRF3R-HSA-3249392 (Reactome)
STING:p-S172-TBK1:IRF3mim-catalysisR-HSA-2396007 (Reactome)
STING:p-S172-TBK1:STAT6ArrowR-HSA-3249390 (Reactome)
STING:p-S172-TBK1:STAT6R-HSA-3249371 (Reactome)
STING:p-S172-TBK1:STAT6mim-catalysisR-HSA-3249371 (Reactome)
STING:p-S172-TBK1ArrowR-HSA-2396007 (Reactome)
STING:p-S172-TBK1ArrowR-HSA-3249371 (Reactome)
TBK1R-HSA-1606324 (Reactome)
TBK1R-HSA-1834939 (Reactome)
TBK1R-HSA-3249378 (Reactome)
TMEM173R-HSA-1964496 (Reactome)
TMEM173R-HSA-3134800 (Reactome)
TMPArrowR-HSA-3245943 (Reactome)
TREX1 dimerArrowR-HSA-3245943 (Reactome)
TREX1 dimerR-HSA-3244605 (Reactome)
TREX1 dimerTBarR-HSA-1834939 (Reactome)
TREX1:viral DNAArrowR-HSA-3244605 (Reactome)
TREX1:viral DNAR-HSA-3245943 (Reactome)
TREX1:viral DNAmim-catalysisR-HSA-3245943 (Reactome)
TRIM21R-HSA-3134946 (Reactome)
TRIM21TBarR-HSA-3134822 (Reactome)
TRIM21mim-catalysisR-HSA-3134946 (Reactome)
TRIM32/TRIM56ArrowR-HSA-3134804 (Reactome)
TRIM32/TRIM56R-HSA-1964496 (Reactome)
UbR-HSA-3134804 (Reactome)
UbR-HSA-3134946 (Reactome)
UbR-HSA-3249386 (Reactome)
UbR-HSA-8948709 (Reactome)
Unmethylated CpG DNAR-HSA-3134954 (Reactome)
Unmethylated CpG DNAR-HSA-3134962 (Reactome)
ZBP1 ligandR-HSA-1591234 (Reactome)
ZBP1R-HSA-1591234 (Reactome)
beta-catenin:IRF3:p300ArrowR-HSA-3134883 (Reactome)
c-GMP-AMPArrowR-HSA-1834939 (Reactome)
c-GMP-AMPArrowR-HSA-3244614 (Reactome)
c-GMP-AMPR-HSA-3244643 (Reactome)
c-di-AMP, c-di-GMPR-HSA-9013869 (Reactome)
c-di-GMPArrowR-HSA-1834939 (Reactome)
c-di-GMPR-HSA-2396009 (Reactome)
cGAS ligandsR-HSA-3244647 (Reactome)
cGAS:dsDNAArrowR-HSA-3244647 (Reactome)
cGAS:dsDNAmim-catalysisR-HSA-3244614 (Reactome)
dCMPArrowR-HSA-3245943 (Reactome)
dsDNA:IFI16ArrowR-HSA-1834939 (Reactome)
dsDNA:IFI16ArrowR-HSA-1834951 (Reactome)
dsDNA:LRR

FLII-interacting

protein 1dimer
ArrowR-HSA-3134896 (Reactome)
dsDNA:LRR

FLII-interacting

protein 1dimer
ArrowR-HSA-3134904 (Reactome)
dsDNA:LRR

FLII-interacting

protein 1dimer
R-HSA-3134901 (Reactome)
dsDNA:LRRFIP1:beta-cateninArrowR-HSA-3134901 (Reactome)
dsDNA:LRRFIP1:beta-cateninR-HSA-3134904 (Reactome)
dsDNA:ZBP1:RIP1:RIP3ArrowR-HSA-168910 (Reactome)
dsDNA:ZBP1:RIP1:RIP3ArrowR-HSA-1810457 (Reactome)
dsDNA:ZBP1:pS-172,K48polyUb-TBK1ArrowR-HSA-3249386 (Reactome)
dsDNA:ZBP1:pS-172-TBK1ArrowR-HSA-1606324 (Reactome)
dsDNA:ZBP1:pS-172-TBK1ArrowR-HSA-1606327 (Reactome)
dsDNA:ZBP1:pS-172-TBK1R-HSA-1606345 (Reactome)
dsDNA:ZBP1:pS-172-TBK1R-HSA-8948703 (Reactome)
dsDNA:ZBP1:pS-172-TBK:IRF3ArrowR-HSA-1606345 (Reactome)
dsDNA:ZBP1:pS-172-TBK:IRF3R-HSA-1606327 (Reactome)
dsDNA:ZBP1ArrowR-HSA-1591234 (Reactome)
dsDNA:ZBP1R-HSA-1606324 (Reactome)
dsDNA:ZBP1R-HSA-1810457 (Reactome)
p-2S-IRF7:p-2S-IRF7R-HSA-9604487 (Reactome)
p-4S,T404-IRF3ArrowR-HSA-1606327 (Reactome)
p-4S,T404-IRF3ArrowR-HSA-2396007 (Reactome)
p-4S,T404-IRF3R-HSA-2395992 (Reactome)
p-S407,Y641-STAT6 dimerArrowR-HSA-3249370 (Reactome)
p-S407,Y641-STAT6 dimerArrowR-HSA-3249372 (Reactome)
p-S407,Y641-STAT6 dimerR-HSA-3249370 (Reactome)
p-S407,Y641-STAT6ArrowR-HSA-3249379 (Reactome)
p-S407,Y641-STAT6R-HSA-3249372 (Reactome)
p-S407-STAT6ArrowR-HSA-3249371 (Reactome)
p-S407-STAT6R-HSA-3249379 (Reactome)
p-S552-CTNNB1ArrowR-HSA-3134904 (Reactome)
p-S552-CTNNB1ArrowR-HSA-3134914 (Reactome)
p-S552-CTNNB1R-HSA-3134883 (Reactome)
p-S552-CTNNB1R-HSA-3134914 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3ArrowR-HSA-2032396 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3ArrowR-HSA-2395992 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3R-HSA-2032396 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3R-HSA-3134883 (Reactome)
viral dsRNA:TLR3:TICAM1:RIPK1ArrowR-HSA-168910 (Reactome)
viral DNA with 3' sticky endsR-HSA-3244605 (Reactome)

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