Cytosolic sensors of pathogen-associated DNA (Homo sapiens)

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7, 47, 789, 2411, 513220, 41343256, 7726, 28, 35, 39, 54...2268, 8039, 8216, 5536, 7119, 29, 3410, 21, 63, 674129, 37, 5214, 53, 80825, 6056, 7736, 71212217, 449, 33, 7935, 73, 75, 7635, 73, 75, 76827, 805612, 801, 15, 18, 35, 38...4029, 34, 35323, 43, 72, 79326, 13214, 55, 64823, 48, 583230, 80Activated IKK Complex HsRPC4HsRPC5 DDX41 ligand S100A12 dimer DDX41 ligand AGER ligands dsDNAZBP1 dsDNALRR FLII-interacting protein 1dimer TREX1viral DNA DNA-PKmicrobial dsDNA STINGp-S172-TBK1IRF3 K48polyUb-DDX41TRIM21 STINGSTING ZBP1ZBP1 microbial dsDNA microbial dsDNA Ku70Ku80 heterodimer STINGTBK1STAT6 STINGTRIM32/TRIM56 p-S407,Y641-STAT6 dimer STINGSTING cytosolp-2S-IRF7p-2S-IRF7 Ku70Ku80 heterodimer viral DNA with 3' sticky ends microbial dsDNA TREX1 dimer DHX9CpG dsDNAZBP1pS-172-TBKIRF3 cGASdsDNA RNA Polymerase III Holoenzyme microbial dsDNA dsDNAZBP1pS-172-TBK1 TRIM32/TRIM56 dsDNAZBP1 NFkB Complex p-T,4S-IRF3p-T,4S-IRF3 LRR FLII-interacting protein 1 dimer Nuclear factor NF-kappa-B STINGSTING Nuclear factor NF-kappa-B RPC7/RPC7-like dsDNAIFI16 p-T,4S-IRF3p-T,4S-IRF3 HsRPC8HsRPC9 endoplasmic reticulummicrobial dsDNA ZBP1ZBP1 DDX41DDX41 ligand STINGp-S172-TBK1 STINGSTING cytoplasmic membrane-bounded vesicle lumendsDNAZBP1 DHX36CpG DHX36CpG STINGTBK1IRF3 S100B homodimer DHX9CpG microbial dsDNA DNA-PKmicrobial dsDNA DHX9CpG STING activators AGER ligandsAGER DHX36CpG viral dsRNA TLR3 NF-kappaB inhibitor NLRP4DTX4p-S172-TBK1complexes STINGcGAMP dsDNALRRFIP1beta-catenin nucleoplasmdsDNAZBP1pS-172-TBK1 DHX9CpGMyD88 viral dsRNATLR3TRIFRIP1 p-S407,Y641-STAT6 dimer p-T,4S-IRF3p-T,4S-IRF3 STINGSTING p-2S-IRF7p-2S-IRF7 DHX9/DHX36CpGMyD88 TREX1 dimer Ku70Ku80 heterodimer AGE adducts IkBsNFkB DHX9/DHX36CpG Nuclear factor NF-kappa-B DHX36CpG MRE11dsDNA DDX41DDX41 ligand MRE11dsDNA IKKAIKKBNEMO viral dsRNATLR3TRIF dsDNAZBP1 microbial dsDNA viral DNA with 3' sticky ends STINGc-di-GMP HsRPC6HsRPC3HsRPC7 NFkB Complex microbial dsDNA DHX36CpGMyD88 DHX9CpG dsDNALRR FLII-interacting protein 1dimer ZBP1ZBP1 STINGSTING STINGSTING DHX36CpGMyD88 beta-cateninIRF3p300 (perinuclear vesicle)K48polyUb-DDX41 LRR FLII-interacting protein 1 dimer LRR FLII-interacting protein 1 dimer STINGSTING ZBP1ZBP1 CBP/p300 NFkB Complex STINGp-S172-TBK1STAT6 DHX9CpGMyD88 dsDNAZBP1RIP1RIP3 STINGSTING microbial dsDNA AGE adductsPeptide dsDNAIFI16 p-T,4S-IRF3p-T,4S-IRF3RIPK3 XRCC6 IKKAIKKBNEMOLRRFIP1STINGSTINGmicrobial dsDNAp-4S,T404-IRF3 STINGSTINGATPPPiRIPK1 STINGp-S172-TBK1IRF3Peptide p-S552-CTNNB1 DHX9 POLR1D MRE11A beta-cateninIRF3p300K63polyUb-STING c-di-GMP PRKDCTRIM32 MYD88 TRIM56 TMPXRCC6 RIG-I/MDA5 mediated induction of IFN-alpha/beta pathwaysc-di-GMPPOLR3H LZTS1 MB21D1DHX36CpGMyD88MYD88XRCC6 NFKB2NFKB1TBK1SAA1p-S172-TBK1 ADPIkBsNFkBp-S172-TBK1 DHX9CpGK63polyUb-STING Phospho-NF-kappaB Inhibitorc-GMP-AMP S100B dGMPATPIRF3 STINGTBK1IRF3UbTREX1 TRIM21 POLR2E RELA bacterial dsDNAdCMPTREX1viral DNAK63polyUb-STING DHX9 p-S552-CTNNB1S100A12 TMEM173 DHX9 ADPIKBKB MYD88 N-epsilon-DHX36CpGdsDNAZBP1pS-172-TBK1p-S477,S479-IRF7 TBK1 K48polyUb-DDX41 TMEM173 AGER ligandsAGERSTAT6 AT-rich dsDNAIFI16 CTNNB1DHX9p-S172-TBK1 complexescGAS ligandSTING activatorsSTINGp-S172-TBK1STAT6POLR3G DHX9/DHX36CpGp-S407-STAT6TRIM32/TRIM56XRCC5 POLR3E POLR3B ATPK63polyUb-STING RNA Polymerase III HoloenzymeTREX1 dimerdAMPDDX41DDX41 ligandATPp-S407,Y641-STAT6DHX9/DHX36CpGMyD88RIPK1IRF3ADPDTX4 Activated IKK ComplexSTAT6 STINGc-di-GMPSTINGTRIM32/TRIM56NFkB ComplexTICAM1 MYD88 ZBP1 RIPK3dsDNAIFI16IKBKG IRF3c-di-GMP p-2S-IRF7p-2S-IRF7K63polyUb-STING CREBBPp-S172-TBK1 DHX36 TREX1 NLRP4DTX4p-S172-TBK1complexesK63polyUb-STING NFKB1ADPc-di-AMP ZBP1 MRE11 ligandPOLR2Fp-S407,Y641-STAT6 NLRP4TRIM21POLR3A dsDNAZBP1pS-172-TBKIRF3p-S407,Y641-STAT6 dimerSTINGcGAMPcGASdsDNANFKBIB Ku70Ku80 heterodimerUbNFKB1STINGp-S172-TBK1DTX4POLR3C H2ONFkB ComplexZBP1 c-di-AMP NFKBIA IKBKG ATPATPNFKB2DHX36 Promotor region of interferon betaXRCC5 ATPNECML IFI16 DNA-PKmicrobial dsDNASTAT6XRCC5 IFI16p-S552-CTNNB1POLR3D DHX36ATPADPp-S172-TBK1 dsDNAZBP1Mg2+AGER ADPZBP1 UbRIPK1 IRF3 PRKDCATPGTPNFKB2dsDNALRRFIP1beta-cateninDDX41POLR2K DDX41 CBP/p300ATPp-S407,Y641-STAT6 Unmethylated CpG DNAADPDHX9CpGMyD88viral DNA with 3' sticky endsPOLR3F K63polyUb-STINGSTINGTBK1STAT6p-S176,S180-CHUK TLR3 LRRFIP1POLR1C MRE11A IRF3 p-S407,Y641-STAT6 dimerviral dsDNAp-S172-TBK1 dsDNAZBP1RIP1RIP3MB21D1 TBK1 p-S177,S181-IKBKB POLR2H K48polyUb-DDX41 p-T,4S-IRF3p-T,4S-IRF3p-4S,T404-IRF3 K63polyUb-STING LRRFIP1ADPADPATPDHX36 TMEM173c-GMP-AMP c-di-GMP 5'-ppp-AU-rich dsRNADDX41 POLR2L MRE11ADHX36 dsDNALRR FLII-interacting protein 1dimerPOLR3K MRE11dsDNADDX41 ligandRELA ZBP1HMGB1 ADPDHX9 APPc-GMP-AMPK48polyUb-DDX41TRIM21p-4S,T404-IRF3EP300Mg2+ NLRP4 LRR FLII-interacting protein 1 dimerp-2S-IRF7p-2S-IRF7RELA APPCTNNB1 viral dsRNATLR3TRIFRIP1POLR3GL TBK1p-S172,K48polyUb-TBK1 complexesPRKDCK63polyUb-STING CHUK p-S477,S479-IRF7 p-4S,T404-IRF3 871223250, 806395583545, 77354, 6469402, 5, 31, 61, 66...41, 598868566832603962, 7435


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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1834949</div>

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  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

View all...
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
5'-ppp-AU-rich dsRNAREACT_164072 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGER ProteinQ15109 (Uniprot-TrEMBL)
AGER ligands AGERComplexREACT_24620 (Reactome)
APPProteinP05067 (Uniprot-TrEMBL)
AT-rich dsDNAREACT_164924 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated IKK ComplexComplexREACT_7826 (Reactome)
CBP/p300ProteinREACT_25880 (Reactome)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
CTNNB1 ProteinP35222 (Uniprot-TrEMBL)
CTNNB1ProteinP35222 (Uniprot-TrEMBL)
DDX41 DDX41 ligandComplexREACT_160900 (Reactome)
DDX41 ProteinQ9UJV9 (Uniprot-TrEMBL)
DDX41 ligandMetaboliteREACT_160922 (Reactome)
DDX41ProteinQ9UJV9 (Uniprot-TrEMBL)
DHX36

CpG

MyD88		ComplexREACT_161245 (Reactome)
DHX36 CpGComplexREACT_160366 (Reactome)
DHX36 ProteinQ9H2U1 (Uniprot-TrEMBL)
DHX36ProteinQ9H2U1 (Uniprot-TrEMBL)
DHX9

CpG

MyD88		ComplexREACT_160421 (Reactome)
DHX9 CpGComplexREACT_164550 (Reactome)
DHX9 ProteinQ08211 (Uniprot-TrEMBL)
DHX9/DHX36

CpG

MyD88		ComplexREACT_164459 (Reactome)
DHX9/DHX36 CpGComplexREACT_165224 (Reactome)
DHX9ProteinQ08211 (Uniprot-TrEMBL)
DNA-PK microbial dsDNAComplexREACT_161385 (Reactome)
DTX4 ProteinQ9Y2E6 (Uniprot-TrEMBL)
DTX4ProteinQ9Y2E6 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HMGB1 ProteinP09429 (Uniprot-TrEMBL)
IFI16 ProteinQ16666 (Uniprot-TrEMBL)
IFI16ProteinQ16666 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA

IKKB

NEMO		ComplexREACT_7693 (Reactome)
IRF3 ProteinQ14653 (Uniprot-TrEMBL)
IRF3ProteinQ14653 (Uniprot-TrEMBL)
IkBs NFkBComplexREACT_7272 (Reactome)
K48polyUb-DDX41 TRIM21ComplexREACT_164901 (Reactome)
K48polyUb-DDX41 ProteinQ9UJV9 (Uniprot-TrEMBL)
K63polyUb-STING ProteinQ86WV6 (Uniprot-TrEMBL)
K63polyUb-STINGProteinQ86WV6 (Uniprot-TrEMBL)
Ku70 Ku80 heterodimerComplexREACT_161331 (Reactome)
LRR FLII-interacting protein 1 dimerComplexREACT_165504 (Reactome)
LRRFIP1ProteinQ32MZ4 (Uniprot-TrEMBL)
LZTS1 ProteinQ9Y250 (Uniprot-TrEMBL)
MB21D1 ProteinQ8N884 (Uniprot-TrEMBL)
MB21D1ProteinQ8N884 (Uniprot-TrEMBL)
MRE11 dsDNAComplexREACT_164808 (Reactome)
MRE11 ligandREACT_165437 (Reactome)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRE11AProteinP49959 (Uniprot-TrEMBL)
MYD88 ProteinQ99836 (Uniprot-TrEMBL)
MYD88ProteinQ99836 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mg2+MetaboliteCHEBI:18420 (ChEBI)
N-epsilon-MetaboliteCHEBI:60125 (ChEBI)
NECML MetaboliteCHEBI:53014 (ChEBI)
NFKB1ProteinP19838 (Uniprot-TrEMBL)
NFKB2ProteinQ00653 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
NFkB ComplexComplexREACT_7108 (Reactome)
NFkB ComplexComplexREACT_7143 (Reactome)
NLRP4

DTX4

p-S172-TBK1complexes		ComplexREACT_164593 (Reactome)
NLRP4 ProteinQ96MN2 (Uniprot-TrEMBL)
NLRP4ProteinQ96MN2 (Uniprot-TrEMBL)
POLR1C ProteinO15160 (Uniprot-TrEMBL)
POLR1D ProteinQ9Y2S0 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2FProteinP61218 (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)
PRKDCProteinP78527 (Uniprot-TrEMBL)
Peptide MetaboliteCHEBI:16670 (ChEBI)
Phospho-NF-kappaB InhibitorREACT_7645 (Reactome)
Promotor region of interferon betaREACT_25836 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathwaysPathwayREACT_25359 (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.
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
RIPK3 ProteinQ9Y572 (Uniprot-TrEMBL)
RIPK3ProteinQ9Y572 (Uniprot-TrEMBL)
RNA Polymerase III HoloenzymeComplexREACT_164450 (Reactome)
S100A12 ProteinP80511 (Uniprot-TrEMBL)
S100B ProteinP04271 (Uniprot-TrEMBL)
SAA1ProteinP0DJI8 (Uniprot-TrEMBL)
STAT6 ProteinP42226 (Uniprot-TrEMBL)
STAT6ProteinP42226 (Uniprot-TrEMBL)
STING STINGComplexREACT_148482 (Reactome)
STING STINGComplexREACT_160695 (Reactome)
STING

TBK1

IRF3		ComplexREACT_148249 (Reactome)
STING

TBK1

STAT6		ComplexREACT_165575 (Reactome)
STING TRIM32/TRIM56ComplexREACT_164587 (Reactome)
STING c-di-GMPComplexREACT_147998 (Reactome)
STING cGAMPComplexREACT_165414 (Reactome)
STING

p-S172-TBK1

IRF3		ComplexREACT_148605 (Reactome)
STING

p-S172-TBK1

STAT6		ComplexREACT_164288 (Reactome)
STING p-S172-TBK1ComplexREACT_148607 (Reactome)
STING activatorsComplexREACT_164315 (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 viral DNAComplexREACT_164408 (Reactome)
TREX1 ProteinQ9NSU2 (Uniprot-TrEMBL)
TREX1 dimerComplexREACT_165268 (Reactome)
TRIM21 ProteinP19474 (Uniprot-TrEMBL)
TRIM21ProteinP19474 (Uniprot-TrEMBL)
TRIM32 ProteinQ13049 (Uniprot-TrEMBL)
TRIM32/TRIM56ProteinREACT_165399 (Reactome)
TRIM56 ProteinQ9BRZ2 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
Unmethylated CpG DNAREACT_161474 (Reactome)
XRCC5 ProteinP13010 (Uniprot-TrEMBL)
XRCC6 ProteinP12956 (Uniprot-TrEMBL)
ZBP1 ProteinQ9H171 (Uniprot-TrEMBL)
ZBP1ProteinQ9H171 (Uniprot-TrEMBL)
bacterial dsDNAREACT_160413 (Reactome)
beta-catenin

IRF3

p300		ComplexREACT_164162 (Reactome)
c-GMP-AMP MetaboliteCHEBI:71580 (ChEBI)
c-GMP-AMPMetaboliteCHEBI:71580 (ChEBI)
c-di-AMP MetaboliteCHEBI:47037 (ChEBI)
c-di-GMP MetaboliteCHEBI:49537 (ChEBI)
c-di-GMPMetaboliteCHEBI:49537 (ChEBI)
cGAS dsDNAComplexREACT_164787 (Reactome)
cGAS ligandMetaboliteREACT_165334 (Reactome)
dAMPMetaboliteCHEBI:17713 (ChEBI)
dCMPMetaboliteCHEBI:15918 (ChEBI)
dGMPMetaboliteCHEBI:16192 (ChEBI)
dsDNA IFI16ComplexREACT_148075 (Reactome)
dsDNA LRR FLII-interacting protein 1dimerComplexREACT_165341 (Reactome)
dsDNA

LRRFIP1

beta-catenin		ComplexREACT_164918 (Reactome)
dsDNA

ZBP1 RIP1

RIP3		ComplexREACT_116701 (Reactome)
dsDNA

ZBP1 pS-172-TBK

IRF3		ComplexREACT_118875 (Reactome)
dsDNA

ZBP1

pS-172-TBK1		ComplexREACT_119373 (Reactome)
dsDNA ZBP1ComplexREACT_116520 (Reactome)
microbial dsDNAMetaboliteREACT_160598 (Reactome)
p-2S-IRF7 p-2S-IRF7ComplexREACT_21640 (Reactome)
p-2S-IRF7 p-2S-IRF7ComplexREACT_21965 (Reactome)
p-4S,T404-IRF3 ProteinQ14653 (Uniprot-TrEMBL)
p-4S,T404-IRF3ProteinQ14653 (Uniprot-TrEMBL)
p-S172,K48polyUb-TBK1 complexesComplexREACT_164137 (Reactome)
p-S172-TBK1 ProteinQ9UHD2 (Uniprot-TrEMBL)
p-S172-TBK1 complexesComplexREACT_165211 (Reactome)
p-S176,S180-CHUK ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S407,Y641-STAT6 ProteinP42226 (Uniprot-TrEMBL)
p-S407,Y641-STAT6 dimerComplexREACT_164683 (Reactome)
p-S407,Y641-STAT6 dimerComplexREACT_165571 (Reactome)
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-IRF3ComplexREACT_7146 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3ComplexREACT_7444 (Reactome)
viral DNA with 3' sticky endsComplexREACT_8181 (Reactome)
viral dsDNAREACT_161032 (Reactome)
viral dsRNA

TLR3 TRIF

RIP1		ComplexREACT_7715 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowREACT_118685 (Reactome)
ADPArrowREACT_118783 (Reactome)
ADPArrowREACT_147769 (Reactome)
ADPArrowREACT_147901 (Reactome)
ADPArrowREACT_163707 (Reactome)
ADPArrowREACT_163766 (Reactome)
ADPArrowREACT_163774 (Reactome)
ADPArrowREACT_163955 (Reactome)
ADPArrowREACT_6848 (Reactome)
ADPArrowREACT_6973 (Reactome)
AGER ligands AGERArrowREACT_6906 (Reactome)
ATPREACT_118685 (Reactome)
ATPREACT_118783 (Reactome)
ATPREACT_147769 (Reactome)
ATPREACT_147901 (Reactome)
ATPREACT_163707 (Reactome)
ATPREACT_163766 (Reactome)
ATPREACT_163774 (Reactome)
ATPREACT_163779 (Reactome)
ATPREACT_163955 (Reactome)
ATPREACT_6848 (Reactome)
ATPREACT_6973 (Reactome)
Activated IKK ComplexArrowREACT_6973 (Reactome)
Activated IKK Complexmim-catalysisREACT_6848 (Reactome)
CBP/p300REACT_163902 (Reactome)
CTNNB1REACT_163821 (Reactome)
DDX41 ligandREACT_163653 (Reactome)
DDX41REACT_163639 (Reactome)
DDX41REACT_163653 (Reactome)
DHX36

CpG

MyD88		ArrowREACT_24920 (Reactome)
DHX36REACT_163740 (Reactome)
DHX9

CpG

MyD88		ArrowREACT_6906 (Reactome)
DHX9/DHX36 CpGREACT_163991 (Reactome)
DHX9REACT_163771 (Reactome)
DTX4ArrowREACT_163856 (Reactome)
DTX4REACT_163683 (Reactome)
GTPREACT_163779 (Reactome)
H2OREACT_163957 (Reactome)
IFI16REACT_147878 (Reactome)
IKKA

IKKB

NEMO		REACT_6973 (Reactome)
IRF3REACT_118613 (Reactome)
IRF3REACT_147703 (Reactome)
IkBs NFkBREACT_6848 (Reactome)
K63polyUb-STINGArrowREACT_163749 (Reactome)
Ku70 Ku80 heterodimerREACT_163719 (Reactome)
LRR FLII-interacting protein 1 dimerREACT_163915 (Reactome)
MB21D1REACT_163636 (Reactome)
MRE11 ligandREACT_163772 (Reactome)
MRE11AREACT_163772 (Reactome)
MYD88REACT_163991 (Reactome)
Mg2+REACT_163654 (Reactome)
NFkB ComplexArrowREACT_6848 (Reactome)
NLRP4

DTX4

p-S172-TBK1complexes		REACT_163856 (Reactome)
NLRP4

DTX4

p-S172-TBK1complexes		TBarREACT_118685 (Reactome)
NLRP4

DTX4

p-S172-TBK1complexes		TBarREACT_147769 (Reactome)
NLRP4

DTX4

p-S172-TBK1complexes		mim-catalysisREACT_163856 (Reactome)
NLRP4ArrowREACT_163856 (Reactome)
NLRP4REACT_163683 (Reactome)
PPiArrowREACT_163779 (Reactome)
PRKDCREACT_163719 (Reactome)
Phospho-NF-kappaB InhibitorArrowREACT_6848 (Reactome)
Promotor region of interferon betaREACT_163902 (Reactome)
REACT_118567 (Reactome) IRF3-P:IRF3-P' is translocated from cytosol to nucleoplasm.
REACT_118613 (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.
REACT_118621 (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).

REACT_118685 (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.
REACT_118783 (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.
REACT_118851 (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).
REACT_147703 (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 H et al. 2009; Saitoh T et al. 2009; Sun W et al. 2009; Tanaka Y and Chen ZJ 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 S et al. 2012].

STING was reported to mediate TBK1-dependent activation of transcription factor IRF3 [Zhong B et al. 2008; Tanaka Y and Chen ZJ 2012]. Both TBK1 and IRF3 can directly interact with STING through its C-terminal region [Tanaka Y and Chen ZJ 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 Y and Chen ZJ 2012]. Thus, STING is thought to function as a scaffold to recruit cytosolic TBK1 and IRF3, which results in TBK1-dependent phosphorylation of IRF3. in TBK1dependent phosphorylation of IRF3. Importantly, though both monomer and dimer STING can bind TBK1, only STING dimer binds TBK1 and activates Type I IFN [Ouyang S et al. 2012].

REACT_147763 (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.

REACT_147769 (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.
REACT_147821 (Reactome) IRF3 phosphorylation promotes IRF3 dimerization and nuclear translocation, which results in the production of type I interferons (IFNs).
REACT_147878 (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].

REACT_147901 (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].
REACT_163630 (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)

REACT_163636 (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.
REACT_163639 (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).

REACT_163653 (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).

REACT_163654 (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).

REACT_163667 (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).
REACT_163668 (Reactome) Phosphorylation of STAT6 results in the homodimerization and nucleus translocation of STAT6 where it binds to the target sites to initiate transcription.
REACT_163683 (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).
REACT_163707 (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].
  • 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.
REACT_163719 (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).

REACT_163740 (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].
REACT_163749 (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.
REACT_163766 (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).
REACT_163771 (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].
REACT_163772 (Reactome) DNA damage sensor, meiotic recombination 11 homolog A (MRE11) has been shown to function as a cytosolic sensor of dsDNA. 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)
REACT_163774 (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.
REACT_163779 (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).
REACT_163797 (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).
REACT_163821 (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).
REACT_163840 (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)

REACT_163856 (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).
REACT_163868 (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).
REACT_163891 (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.
REACT_163897 (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.

REACT_163902 (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.
REACT_163915 (Reactome) LRRFIP1 can recognize both AT-rich B-form dsDNA and GC-rich Z-form dsDNA (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).
REACT_163955 (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).
REACT_163957 (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).
REACT_163991 (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].

REACT_24920 (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.
REACT_6848 (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.

REACT_6906 (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. Therefor, 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.
REACT_6973 (Reactome)
  • In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination.

    This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs.

    IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.

  • 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).

RIPK1REACT_118851 (Reactome)
RIPK3REACT_118851 (Reactome)
RNA Polymerase III Holoenzymemim-catalysisREACT_163897 (Reactome)
STAT6REACT_163667 (Reactome)
STING STINGREACT_147703 (Reactome)
STING STINGREACT_147763 (Reactome)
STING STINGREACT_163667 (Reactome)
STING STINGREACT_163868 (Reactome)
STING

TBK1

IRF3		REACT_147901 (Reactome)
STING

TBK1

STAT6		REACT_163707 (Reactome)
STING TRIM32/TRIM56REACT_163749 (Reactome)
STING TRIM32/TRIM56mim-catalysisREACT_163749 (Reactome)
STING

p-S172-TBK1

IRF3		ArrowREACT_147901 (Reactome)
STING

p-S172-TBK1

IRF3		REACT_147769 (Reactome)
STING

p-S172-TBK1

IRF3		mim-catalysisREACT_147769 (Reactome)
STING

p-S172-TBK1

STAT6		ArrowREACT_163707 (Reactome)
STING

p-S172-TBK1

STAT6		REACT_163955 (Reactome)
STING

p-S172-TBK1

STAT6		mim-catalysisREACT_163955 (Reactome)
STING p-S172-TBK1ArrowREACT_147769 (Reactome)
STING p-S172-TBK1ArrowREACT_163955 (Reactome)
STING activatorsArrowREACT_147703 (Reactome)
TBK1REACT_118783 (Reactome)
TBK1REACT_147703 (Reactome)
TBK1REACT_163667 (Reactome)
TMEM173REACT_163797 (Reactome)
TMPArrowREACT_163957 (Reactome)
TREX1 viral DNAREACT_163957 (Reactome)
TREX1 viral DNAmim-catalysisREACT_163957 (Reactome)
TREX1 dimerArrowREACT_163957 (Reactome)
TREX1 dimerREACT_163654 (Reactome)
TREX1 dimerTBarREACT_147703 (Reactome)
TRIM21REACT_163639 (Reactome)
TRIM21TBarREACT_163653 (Reactome)
TRIM21mim-catalysisREACT_163639 (Reactome)
TRIM32/TRIM56ArrowREACT_163749 (Reactome)
TRIM32/TRIM56REACT_163797 (Reactome)
UbREACT_163639 (Reactome)
UbREACT_163749 (Reactome)
UbREACT_163856 (Reactome)
Unmethylated CpG DNAREACT_163740 (Reactome)
Unmethylated CpG DNAREACT_163771 (Reactome)
ZBP1REACT_118621 (Reactome)
c-GMP-AMPArrowREACT_163779 (Reactome)
c-GMP-AMPREACT_163868 (Reactome)
c-di-GMPREACT_147763 (Reactome)
cGAS dsDNAmim-catalysisREACT_163779 (Reactome)
cGAS ligandREACT_163636 (Reactome)
dAMPArrowREACT_163957 (Reactome)
dCMPArrowREACT_163957 (Reactome)
dGMPArrowREACT_163957 (Reactome)
dsDNA LRR FLII-interacting protein 1dimerArrowREACT_163774 (Reactome)
dsDNA LRR FLII-interacting protein 1dimerREACT_163821 (Reactome)
dsDNA

LRRFIP1

beta-catenin		REACT_163774 (Reactome)
dsDNA

ZBP1 RIP1

RIP3		ArrowREACT_6973 (Reactome)
dsDNA

ZBP1 pS-172-TBK

IRF3		REACT_118685 (Reactome)
dsDNA

ZBP1

pS-172-TBK1		ArrowREACT_118685 (Reactome)
dsDNA

ZBP1

pS-172-TBK1		ArrowREACT_118783 (Reactome)
dsDNA

ZBP1

pS-172-TBK1		REACT_118613 (Reactome)
dsDNA ZBP1REACT_118783 (Reactome)
dsDNA ZBP1REACT_118851 (Reactome)
microbial dsDNAREACT_118621 (Reactome)
microbial dsDNAREACT_163719 (Reactome)
microbial dsDNAREACT_163915 (Reactome)
p-4S,T404-IRF3ArrowREACT_118685 (Reactome)
p-4S,T404-IRF3ArrowREACT_147769 (Reactome)
p-S172,K48polyUb-TBK1 complexesArrowREACT_163856 (Reactome)
p-S172-TBK1 complexesREACT_163683 (Reactome)
p-S407,Y641-STAT6ArrowREACT_163766 (Reactome)
p-S407-STAT6ArrowREACT_163955 (Reactome)
p-S407-STAT6REACT_163766 (Reactome)
p-S552-CTNNB1ArrowREACT_163774 (Reactome)
p-S552-CTNNB1REACT_163902 (Reactome)
p-T,4S-IRF3 p-T,4S-IRF3REACT_163902 (Reactome)
viral DNA with 3' sticky endsREACT_163654 (Reactome)
viral dsDNAREACT_147878 (Reactome)
viral dsRNA

TLR3 TRIF

RIP1		ArrowREACT_6973 (Reactome)

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