Cytosolic sensors of pathogen-associated DNA (Homo sapiens)

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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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75. Watson RO, Bell SL, MacDuff DA, Kimmey JM, Diner EJ, Olivas J, Vance RE, Stallings CL, Virgin HW, Cox JS.; ''The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy.''; PubMed Europe PMC Scholia
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History

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Compare	Revision	Action	Time	User	Comment
	112538	view	15:50, 9 October 2020	ReactomeTeam	Reactome version 73
	101451	view	11:32, 1 November 2018	ReactomeTeam	reactome version 66
	100989	view	21:10, 31 October 2018	ReactomeTeam	reactome version 65
	100525	view	19:44, 31 October 2018	ReactomeTeam	reactome version 64
	100072	view	16:28, 31 October 2018	ReactomeTeam	reactome version 63
	99623	view	15:01, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
	99230	view	12:44, 31 October 2018	ReactomeTeam	reactome version 62
	94006	view	13:50, 16 August 2017	ReactomeTeam	reactome version 61
	93618	view	11:28, 9 August 2017	ReactomeTeam	reactome version 61
	87165	view	19:20, 18 July 2016	Mkutmon	Ontology Term : 'immune response pathway' added !
	86726	view	09:24, 11 July 2016	ReactomeTeam	reactome version 56
	83421	view	11:11, 18 November 2015	ReactomeTeam	Version54
	81624	view	13:10, 21 August 2015	ReactomeTeam	Version53
	77085	view	08:38, 17 July 2014	ReactomeTeam	Fixed remaining interactions
	76790	view	12:15, 16 July 2014	ReactomeTeam	Fixed remaining interactions
	76113	view	10:17, 11 June 2014	ReactomeTeam	Re-fixing comment source
	75825	view	11:38, 10 June 2014	ReactomeTeam	Reactome 48 Update
	75187	view	09:37, 9 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
	74826	view	10:04, 30 April 2014	ReactomeTeam	Reactome46
	74822	view	08:55, 30 April 2014	ReactomeTeam	New pathway

External references

DataNodes

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Name	Type	Database reference	Comment
5'-ppp-AU-rich dsRNA		REACT_164072 (Reactome)
ADP	Metabolite	CHEBI:16761 (ChEBI)
AGER [plasma membrane]	Protein	Q15109 (Uniprot-TrEMBL)
AGER ligands:AGER	Complex	REACT_24620 (Reactome)
APP(672-711) [extracellular region]	Protein	P05067 (Uniprot-TrEMBL)
APP(672-713) [extracellular region]	Protein	P05067 (Uniprot-TrEMBL)
AT-rich dsDNA		REACT_164924 (Reactome)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated IKK Complex	Complex	REACT_7826 (Reactome)
CBP/p300	Protein	REACT_25880 (Reactome)
CHUK [cytosol]	Protein	O15111 (Uniprot-TrEMBL)
CREBBP(2-2442) [nucleoplasm]	Protein	Q92793 (Uniprot-TrEMBL)
CTNNB1 [cytosol]	Protein	P35222 (Uniprot-TrEMBL)
CTNNB1	Protein	P35222 (Uniprot-TrEMBL)
DDX41 [cytosol]	Protein	Q9UJV9 (Uniprot-TrEMBL)
DDX41 ligand	Metabolite	REACT_160922 (Reactome)
DDX41:DDX41 ligand	Complex	REACT_160900 (Reactome)
DDX41	Protein	Q9UJV9 (Uniprot-TrEMBL)
DHX36 [cytosol]	Protein	Q9H2U1 (Uniprot-TrEMBL)
DHX36:CpG:MyD88	Complex	REACT_161245 (Reactome)
DHX36:CpG	Complex	REACT_160366 (Reactome)
DHX36	Protein	Q9H2U1 (Uniprot-TrEMBL)
DHX9 [cytosol]	Protein	Q08211 (Uniprot-TrEMBL)
DHX9/DHX36:CpG:MyD88	Complex	REACT_164459 (Reactome)
DHX9/DHX36:CpG	Complex	REACT_165224 (Reactome)
DHX9:CpG:MyD88	Complex	REACT_160421 (Reactome)
DHX9:CpG	Complex	REACT_164550 (Reactome)
DHX9	Protein	Q08211 (Uniprot-TrEMBL)
DNA-PK:microbial dsDNA	Complex	REACT_161385 (Reactome)
DTX4 [cytosol]	Protein	Q9Y2E6 (Uniprot-TrEMBL)
DTX4	Protein	Q9Y2E6 (Uniprot-TrEMBL)
EP300(1-2414) [nucleoplasm]	Protein	Q09472 (Uniprot-TrEMBL)
GTP	Metabolite	CHEBI:15996 (ChEBI)
H2O	Metabolite	CHEBI:15377 (ChEBI)
HMGB1 [extracellular region]	Protein	P09429 (Uniprot-TrEMBL)
IFI16 [cytosol]	Protein	Q16666 (Uniprot-TrEMBL)
IFI16	Protein	Q16666 (Uniprot-TrEMBL)
IKBKB [cytosol]	Protein	O14920 (Uniprot-TrEMBL)
IKBKG [cytosol]	Protein	Q9Y6K9 (Uniprot-TrEMBL)
IKKA:IKKB:NEMO	Complex	REACT_7693 (Reactome)
IRF3 [cytosol]	Protein	Q14653 (Uniprot-TrEMBL)
IRF3	Protein	Q14653 (Uniprot-TrEMBL)
IkBs:NFkB	Complex	REACT_7272 (Reactome)
K48polyUb-DDX41 [cytosol]	Protein	Q9UJV9 (Uniprot-TrEMBL)
K48polyUb-DDX41:TRIM21	Complex	REACT_164901 (Reactome)
K63polyUb-STING [cytoplasmic vesicle membrane]	Protein	Q86WV6 (Uniprot-TrEMBL)
K63polyUb-STING	Protein	Q86WV6 (Uniprot-TrEMBL)
Ku70:Ku80 heterodimer	Complex	REACT_161331 (Reactome)
LRR FLII-interacting protein 1 dimer	Complex	REACT_165504 (Reactome)
LRRFIP1(1-808) [cytosol]	Protein	Q32MZ4 (Uniprot-TrEMBL)
LZTS1 [cytosol]	Protein	Q9Y250 (Uniprot-TrEMBL)
MB21D1 [cytosol]	Protein	Q8N884 (Uniprot-TrEMBL)
MB21D1	Protein	Q8N884 (Uniprot-TrEMBL)
MRE11 ligand		REACT_165437 (Reactome)
MRE11:dsDNA	Complex	REACT_164808 (Reactome)
MRE11A [cytosol]	Protein	P49959 (Uniprot-TrEMBL)
MRE11A	Protein	P49959 (Uniprot-TrEMBL)
MYD88 [cytosol]	Protein	Q99836 (Uniprot-TrEMBL)
MYD88	Protein	Q99836 (Uniprot-TrEMBL)
Mg2+ [cytosol]	Metabolite	CHEBI:18420 (ChEBI)
Mg2+	Metabolite	CHEBI:18420 (ChEBI)
N-epsilon-(1-(1-carboxy)ethyl)lysine [extracellular region]	Metabolite	CHEBI:60125 (ChEBI)
NECML [extracellular region]	Metabolite	CHEBI:53014 (ChEBI)
NFKB1(1-433) [cytosol]	Protein	P19838 (Uniprot-TrEMBL)
NFKB1(1-433) [nucleoplasm]	Protein	P19838 (Uniprot-TrEMBL)
NFKB2(1-454) [cytosol]	Protein	Q00653 (Uniprot-TrEMBL)
NFKB2(1-454) [nucleoplasm]	Protein	Q00653 (Uniprot-TrEMBL)
NFKBIA [cytosol]	Protein	P25963 (Uniprot-TrEMBL)
NFKBIB [cytosol]	Protein	Q15653 (Uniprot-TrEMBL)
NFkB Complex	Complex	REACT_7108 (Reactome)
NFkB Complex	Complex	REACT_7143 (Reactome)
NLRP4 [cytosol]	Protein	Q96MN2 (Uniprot-TrEMBL)
NLRP4:DTX4:p-S172-TBK1complexes	Complex	REACT_164593 (Reactome)
NLRP4	Protein	Q96MN2 (Uniprot-TrEMBL)
POLR1C [cytosol]	Protein	O15160 (Uniprot-TrEMBL)
POLR1D [cytosol]	Protein	Q9Y2S0 (Uniprot-TrEMBL)
POLR2E [cytosol]	Protein	P19388 (Uniprot-TrEMBL)
POLR2F(1-127) [cytosol]	Protein	P61218 (Uniprot-TrEMBL)
POLR2H [cytosol]	Protein	P52434 (Uniprot-TrEMBL)
POLR2K [cytosol]	Protein	P53803 (Uniprot-TrEMBL)
POLR2L [cytosol]	Protein	P62875 (Uniprot-TrEMBL)
POLR3A [cytosol]	Protein	O14802 (Uniprot-TrEMBL)
POLR3B [cytosol]	Protein	Q9NW08 (Uniprot-TrEMBL)
POLR3C [cytosol]	Protein	Q9BUI4 (Uniprot-TrEMBL)
POLR3D [cytosol]	Protein	P05423 (Uniprot-TrEMBL)
POLR3E [cytosol]	Protein	Q9NVU0 (Uniprot-TrEMBL)
POLR3F [cytosol]	Protein	Q9H1D9 (Uniprot-TrEMBL)
POLR3G [cytosol]	Protein	O15318 (Uniprot-TrEMBL)
POLR3GL [cytosol]	Protein	Q9BT43 (Uniprot-TrEMBL)
POLR3H [cytosol]	Protein	Q9Y535 (Uniprot-TrEMBL)
POLR3K [cytosol]	Protein	Q9Y2Y1 (Uniprot-TrEMBL)
PPi	Metabolite	CHEBI:29888 (ChEBI)
PRKDC(2-4128) [cytosol]	Protein	P78527 (Uniprot-TrEMBL)
PRKDC(2-4128)	Protein	P78527 (Uniprot-TrEMBL)
Peptide [extracellular region]	Metabolite	CHEBI:16670 (ChEBI)
Phospho-NF-kappaB Inhibitor		REACT_7645 (Reactome)
Promotor region of interferon beta		REACT_25836 (Reactome)
RELA [cytosol]	Protein	Q04206 (Uniprot-TrEMBL)
RELA [nucleoplasm]	Protein	Q04206 (Uniprot-TrEMBL)
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways	Pathway	WP1904 (WikiPathways)	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 [cytosol]	Protein	Q13546 (Uniprot-TrEMBL)
RIPK1 [endosome membrane]	Protein	Q13546 (Uniprot-TrEMBL)
RIPK1	Protein	Q13546 (Uniprot-TrEMBL)
RIPK3 [cytosol]	Protein	Q9Y572 (Uniprot-TrEMBL)
RIPK3	Protein	Q9Y572 (Uniprot-TrEMBL)
RNA Polymerase III Holoenzyme	Complex	REACT_164450 (Reactome)
S100A12 [extracellular region]	Protein	P80511 (Uniprot-TrEMBL)
S100B [extracellular region]	Protein	P04271 (Uniprot-TrEMBL)
SAA1(19-122) [extracellular region]	Protein	P0DJI8 (Uniprot-TrEMBL)
STAT6 [cytosol]	Protein	P42226 (Uniprot-TrEMBL)
STAT6	Protein	P42226 (Uniprot-TrEMBL)
STING activators	Complex	REACT_164315 (Reactome)
STING:STING	Complex	REACT_148482 (Reactome)
STING:STING	Complex	REACT_160695 (Reactome)
STING:TBK1:IRF3	Complex	REACT_148249 (Reactome)
STING:TBK1:STAT6	Complex	REACT_165575 (Reactome)
STING:TRIM32/TRIM56	Complex	REACT_164587 (Reactome)
STING:c-di-GMP	Complex	REACT_147998 (Reactome)
STING:cGAMP	Complex	REACT_165414 (Reactome)
STING:p-S172-TBK1:IRF3	Complex	REACT_148605 (Reactome)
STING:p-S172-TBK1:STAT6	Complex	REACT_164288 (Reactome)
STING:p-S172-TBK1	Complex	REACT_148607 (Reactome)
TBK1 [cytosol]	Protein	Q9UHD2 (Uniprot-TrEMBL)
TBK1	Protein	Q9UHD2 (Uniprot-TrEMBL)
TICAM1 [endosome membrane]	Protein	Q8IUC6 (Uniprot-TrEMBL)
TLR3 [endosome membrane]	Protein	O15455 (Uniprot-TrEMBL)
TMEM173 [endoplasmic reticulum membrane]	Protein	Q86WV6 (Uniprot-TrEMBL)
TMEM173	Protein	Q86WV6 (Uniprot-TrEMBL)
TMP	Metabolite	CHEBI:17013 (ChEBI)
TREX1 [endoplasmic reticulum membrane]	Protein	Q9NSU2 (Uniprot-TrEMBL)
TREX1 dimer	Complex	REACT_165268 (Reactome)
TREX1:viral DNA	Complex	REACT_164408 (Reactome)
TRIM21 [cytosol]	Protein	P19474 (Uniprot-TrEMBL)
TRIM21	Protein	P19474 (Uniprot-TrEMBL)
TRIM32 [cytosol]	Protein	Q13049 (Uniprot-TrEMBL)
TRIM32/TRIM56	Protein	REACT_165399 (Reactome)
TRIM56 [cytosol]	Protein	Q9BRZ2 (Uniprot-TrEMBL)
Ub	Protein	REACT_3316 (Reactome)
Unmethylated CpG DNA		REACT_161474 (Reactome)
XRCC5 [cytosol]	Protein	P13010 (Uniprot-TrEMBL)
XRCC6 [cytosol]	Protein	P12956 (Uniprot-TrEMBL)
ZBP1 [cytosol]	Protein	Q9H171 (Uniprot-TrEMBL)
ZBP1	Protein	Q9H171 (Uniprot-TrEMBL)
bacterial dsDNA		REACT_160413 (Reactome)
beta-catenin:IRF3:p300	Complex	REACT_164162 (Reactome)
c-GMP-AMP [cytosol]	Metabolite	CHEBI:71580 (ChEBI)
c-GMP-AMP	Metabolite	CHEBI:71580 (ChEBI)
c-di-AMP [cytosol]	Metabolite	CHEBI:47037 (ChEBI)
c-di-GMP [cytosol]	Metabolite	CHEBI:49537 (ChEBI)
c-di-GMP	Metabolite	CHEBI:49537 (ChEBI)
cGAS ligand	Metabolite	REACT_165334 (Reactome)
cGAS:dsDNA	Complex	REACT_164787 (Reactome)
dAMP	Metabolite	CHEBI:17713 (ChEBI)
dCMP	Metabolite	CHEBI:15918 (ChEBI)
dGMP	Metabolite	CHEBI:16192 (ChEBI)
dsDNA:IFI16	Complex	REACT_148075 (Reactome)
dsDNA:LRR FLII-interacting protein 1dimer	Complex	REACT_165341 (Reactome)
dsDNA:LRRFIP1:beta-catenin	Complex	REACT_164918 (Reactome)
dsDNA:ZBP1:RIP1:RIP3	Complex	REACT_116701 (Reactome)
dsDNA:ZBP1:pS-172-TBK1	Complex	REACT_119373 (Reactome)
dsDNA:ZBP1:pS-172-TBK:IRF3	Complex	REACT_118875 (Reactome)
dsDNA:ZBP1	Complex	REACT_116520 (Reactome)
microbial dsDNA	Metabolite	REACT_160598 (Reactome)
p-2S-IRF7:p-2S-IRF7	Complex	REACT_21640 (Reactome)
p-2S-IRF7:p-2S-IRF7	Complex	REACT_21965 (Reactome)
p-4S,T404-IRF3 [cytosol]	Protein	Q14653 (Uniprot-TrEMBL)
p-4S,T404-IRF3 [nucleoplasm]	Protein	Q14653 (Uniprot-TrEMBL)
p-4S,T404-IRF3	Protein	Q14653 (Uniprot-TrEMBL)
p-S172,K48polyUb-TBK1 complexes	Complex	REACT_164137 (Reactome)
p-S172-TBK1 [cytosol]	Protein	Q9UHD2 (Uniprot-TrEMBL)
p-S172-TBK1 complexes	Complex	REACT_165211 (Reactome)
p-S176,S180-CHUK [cytosol]	Protein	O15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB [cytosol]	Protein	O14920 (Uniprot-TrEMBL)
p-S407,Y641-STAT6 [cytosol]	Protein	P42226 (Uniprot-TrEMBL)
p-S407,Y641-STAT6 [nucleoplasm]	Protein	P42226 (Uniprot-TrEMBL)
p-S407,Y641-STAT6 dimer	Complex	REACT_164683 (Reactome)
p-S407,Y641-STAT6 dimer	Complex	REACT_165571 (Reactome)
p-S407,Y641-STAT6	Protein	P42226 (Uniprot-TrEMBL)
p-S407-STAT6	Protein	P42226 (Uniprot-TrEMBL)
p-S477,S479-IRF7 [cytosol]	Protein	Q92985 (Uniprot-TrEMBL)
p-S477,S479-IRF7 [nucleoplasm]	Protein	Q92985 (Uniprot-TrEMBL)
p-S552-CTNNB1 [nucleoplasm]	Protein	P35222 (Uniprot-TrEMBL)
p-S552-CTNNB1	Protein	P35222 (Uniprot-TrEMBL)
p-T,4S-IRF3:p-T,4S-IRF3	Complex	REACT_7146 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3	Complex	REACT_7444 (Reactome)
viral dsRNA:TLR3:TRIF:RIP1	Complex	REACT_7715 (Reactome)
viral DNA with 3' sticky ends	Complex	REACT_8181 (Reactome)
viral dsDNA		REACT_161032 (Reactome)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
	5'-ppp-AU-rich dsRNA	Arrow	REACT_163897 (Reactome)
	ADP	Arrow	REACT_118685 (Reactome)
	ADP	Arrow	REACT_118783 (Reactome)
	ADP	Arrow	REACT_147769 (Reactome)
	ADP	Arrow	REACT_147901 (Reactome)
	ADP	Arrow	REACT_163707 (Reactome)
	ADP	Arrow	REACT_163766 (Reactome)
	ADP	Arrow	REACT_163774 (Reactome)
	ADP	Arrow	REACT_163955 (Reactome)
	ADP	Arrow	REACT_6848 (Reactome)
	ADP	Arrow	REACT_6973 (Reactome)
AGER ligands:AGER		Arrow	REACT_6906 (Reactome)
AT-rich dsDNA			REACT_163897 (Reactome)
ATP			REACT_118685 (Reactome)
ATP			REACT_118783 (Reactome)
ATP			REACT_147769 (Reactome)
ATP			REACT_147901 (Reactome)
ATP			REACT_163707 (Reactome)
ATP			REACT_163766 (Reactome)
ATP			REACT_163774 (Reactome)
ATP			REACT_163779 (Reactome)
ATP			REACT_163955 (Reactome)
ATP			REACT_6848 (Reactome)
ATP			REACT_6973 (Reactome)
	Activated IKK Complex	Arrow	REACT_6973 (Reactome)
Activated IKK Complex		mim-catalysis	REACT_6848 (Reactome)
CBP/p300			REACT_163902 (Reactome)
CTNNB1			REACT_163821 (Reactome)
DDX41 ligand			REACT_163653 (Reactome)
	DDX41:DDX41 ligand	Arrow	REACT_163653 (Reactome)
DDX41			REACT_163639 (Reactome)
DDX41			REACT_163653 (Reactome)
DHX36:CpG:MyD88		Arrow	REACT_24920 (Reactome)
	DHX36:CpG	Arrow	REACT_163740 (Reactome)
DHX36			REACT_163740 (Reactome)
	DHX9/DHX36:CpG:MyD88	Arrow	REACT_163991 (Reactome)
DHX9/DHX36:CpG			REACT_163991 (Reactome)
DHX9:CpG:MyD88		Arrow	REACT_6906 (Reactome)
	DHX9:CpG	Arrow	REACT_163771 (Reactome)
DHX9			REACT_163771 (Reactome)
	DNA-PK:microbial dsDNA	Arrow	REACT_163719 (Reactome)
	DTX4	Arrow	REACT_163856 (Reactome)
DTX4			REACT_163683 (Reactome)
GTP			REACT_163779 (Reactome)
H2O			REACT_163957 (Reactome)
IFI16			REACT_147878 (Reactome)
IKKA:IKKB:NEMO			REACT_6973 (Reactome)
IRF3			REACT_118613 (Reactome)
IRF3			REACT_147703 (Reactome)
IkBs:NFkB			REACT_6848 (Reactome)
	K48polyUb-DDX41:TRIM21	Arrow	REACT_163639 (Reactome)
	K63polyUb-STING	Arrow	REACT_163749 (Reactome)
Ku70:Ku80 heterodimer			REACT_163719 (Reactome)
LRR FLII-interacting protein 1 dimer			REACT_163915 (Reactome)
MB21D1			REACT_163636 (Reactome)
MRE11 ligand			REACT_163772 (Reactome)
	MRE11:dsDNA	Arrow	REACT_163772 (Reactome)
MRE11A			REACT_163772 (Reactome)
MYD88			REACT_163991 (Reactome)
Mg2+			REACT_163654 (Reactome)
	NFkB Complex	Arrow	REACT_6848 (Reactome)
	NFkB Complex	Arrow	REACT_6906 (Reactome)
NFkB Complex			REACT_6906 (Reactome)
	NLRP4:DTX4:p-S172-TBK1complexes	Arrow	REACT_163683 (Reactome)
NLRP4:DTX4:p-S172-TBK1complexes			REACT_163856 (Reactome)
NLRP4:DTX4:p-S172-TBK1complexes		TBar	REACT_118685 (Reactome)
NLRP4:DTX4:p-S172-TBK1complexes		TBar	REACT_147769 (Reactome)
NLRP4:DTX4:p-S172-TBK1complexes		mim-catalysis	REACT_163856 (Reactome)
	NLRP4	Arrow	REACT_163856 (Reactome)
NLRP4			REACT_163683 (Reactome)
	PPi	Arrow	REACT_163779 (Reactome)
PRKDC(2-4128)			REACT_163719 (Reactome)
	Phospho-NF-kappaB Inhibitor	Arrow	REACT_6848 (Reactome)
Promotor region of interferon beta			REACT_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)	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)	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).
RIPK1			REACT_118851 (Reactome)
RIPK3			REACT_118851 (Reactome)
RNA Polymerase III Holoenzyme		mim-catalysis	REACT_163897 (Reactome)
STAT6			REACT_163667 (Reactome)
STING activators		Arrow	REACT_147703 (Reactome)
	STING:STING	Arrow	REACT_163630 (Reactome)
STING:STING			REACT_147703 (Reactome)
STING:STING			REACT_147763 (Reactome)
STING:STING			REACT_163667 (Reactome)
STING:STING			REACT_163868 (Reactome)
	STING:TBK1:IRF3	Arrow	REACT_147703 (Reactome)
STING:TBK1:IRF3			REACT_147901 (Reactome)
	STING:TBK1:STAT6	Arrow	REACT_163667 (Reactome)
STING:TBK1:STAT6			REACT_163707 (Reactome)
	STING:TRIM32/TRIM56	Arrow	REACT_163797 (Reactome)
STING:TRIM32/TRIM56			REACT_163749 (Reactome)
STING:TRIM32/TRIM56		mim-catalysis	REACT_163749 (Reactome)
	STING:c-di-GMP	Arrow	REACT_147763 (Reactome)
	STING:cGAMP	Arrow	REACT_163868 (Reactome)
	STING:p-S172-TBK1:IRF3	Arrow	REACT_147901 (Reactome)
STING:p-S172-TBK1:IRF3			REACT_147769 (Reactome)
STING:p-S172-TBK1:IRF3		mim-catalysis	REACT_147769 (Reactome)
	STING:p-S172-TBK1:STAT6	Arrow	REACT_163707 (Reactome)
STING:p-S172-TBK1:STAT6			REACT_163955 (Reactome)
STING:p-S172-TBK1:STAT6		mim-catalysis	REACT_163955 (Reactome)
	STING:p-S172-TBK1	Arrow	REACT_147769 (Reactome)
	STING:p-S172-TBK1	Arrow	REACT_163955 (Reactome)
TBK1			REACT_118783 (Reactome)
TBK1			REACT_147703 (Reactome)
TBK1			REACT_163667 (Reactome)
TMEM173			REACT_163630 (Reactome)
TMEM173			REACT_163797 (Reactome)
	TMP	Arrow	REACT_163957 (Reactome)
	TREX1 dimer	Arrow	REACT_163957 (Reactome)
TREX1 dimer			REACT_163654 (Reactome)
TREX1 dimer		TBar	REACT_147703 (Reactome)
	TREX1:viral DNA	Arrow	REACT_163654 (Reactome)
TREX1:viral DNA			REACT_163957 (Reactome)
TREX1:viral DNA		mim-catalysis	REACT_163957 (Reactome)
TRIM21			REACT_163639 (Reactome)
TRIM21		TBar	REACT_163653 (Reactome)
TRIM21		mim-catalysis	REACT_163639 (Reactome)
	TRIM32/TRIM56	Arrow	REACT_163749 (Reactome)
TRIM32/TRIM56			REACT_163797 (Reactome)
Ub			REACT_163639 (Reactome)
Ub			REACT_163749 (Reactome)
Ub			REACT_163856 (Reactome)
Unmethylated CpG DNA			REACT_163740 (Reactome)
Unmethylated CpG DNA			REACT_163771 (Reactome)
ZBP1			REACT_118621 (Reactome)
	beta-catenin:IRF3:p300	Arrow	REACT_163902 (Reactome)
	c-GMP-AMP	Arrow	REACT_163779 (Reactome)
c-GMP-AMP			REACT_163868 (Reactome)
c-di-GMP			REACT_147763 (Reactome)
cGAS ligand			REACT_163636 (Reactome)
	cGAS:dsDNA	Arrow	REACT_163636 (Reactome)
cGAS:dsDNA		mim-catalysis	REACT_163779 (Reactome)
	dAMP	Arrow	REACT_163957 (Reactome)
	dCMP	Arrow	REACT_163957 (Reactome)
	dGMP	Arrow	REACT_163957 (Reactome)
	dsDNA:IFI16	Arrow	REACT_147878 (Reactome)
	dsDNA:LRR FLII-interacting protein 1dimer	Arrow	REACT_163774 (Reactome)
	dsDNA:LRR FLII-interacting protein 1dimer	Arrow	REACT_163915 (Reactome)
dsDNA:LRR FLII-interacting protein 1dimer			REACT_163821 (Reactome)
	dsDNA:LRRFIP1:beta-catenin	Arrow	REACT_163821 (Reactome)
dsDNA:LRRFIP1:beta-catenin			REACT_163774 (Reactome)
	dsDNA:ZBP1:RIP1:RIP3	Arrow	REACT_118851 (Reactome)
dsDNA:ZBP1:RIP1:RIP3		Arrow	REACT_6973 (Reactome)
	dsDNA:ZBP1:pS-172-TBK1	Arrow	REACT_118685 (Reactome)
	dsDNA:ZBP1:pS-172-TBK1	Arrow	REACT_118783 (Reactome)
dsDNA:ZBP1:pS-172-TBK1			REACT_118613 (Reactome)
	dsDNA:ZBP1:pS-172-TBK:IRF3	Arrow	REACT_118613 (Reactome)
dsDNA:ZBP1:pS-172-TBK:IRF3			REACT_118685 (Reactome)
	dsDNA:ZBP1	Arrow	REACT_118621 (Reactome)
dsDNA:ZBP1			REACT_118783 (Reactome)
dsDNA:ZBP1			REACT_118851 (Reactome)
microbial dsDNA			REACT_118621 (Reactome)
microbial dsDNA			REACT_163719 (Reactome)
microbial dsDNA			REACT_163915 (Reactome)
	p-2S-IRF7:p-2S-IRF7	Arrow	REACT_24920 (Reactome)
p-2S-IRF7:p-2S-IRF7			REACT_24920 (Reactome)
	p-4S,T404-IRF3	Arrow	REACT_118685 (Reactome)
	p-4S,T404-IRF3	Arrow	REACT_147769 (Reactome)
p-4S,T404-IRF3			REACT_147821 (Reactome)
	p-S172,K48polyUb-TBK1 complexes	Arrow	REACT_163856 (Reactome)
p-S172-TBK1 complexes			REACT_163683 (Reactome)
	p-S407,Y641-STAT6 dimer	Arrow	REACT_163668 (Reactome)
	p-S407,Y641-STAT6 dimer	Arrow	REACT_163891 (Reactome)
p-S407,Y641-STAT6 dimer			REACT_163891 (Reactome)
	p-S407,Y641-STAT6	Arrow	REACT_163766 (Reactome)
p-S407,Y641-STAT6			REACT_163668 (Reactome)
	p-S407-STAT6	Arrow	REACT_163955 (Reactome)
p-S407-STAT6			REACT_163766 (Reactome)
	p-S552-CTNNB1	Arrow	REACT_163774 (Reactome)
	p-S552-CTNNB1	Arrow	REACT_163840 (Reactome)
p-S552-CTNNB1			REACT_163840 (Reactome)
p-S552-CTNNB1			REACT_163902 (Reactome)
	p-T,4S-IRF3:p-T,4S-IRF3	Arrow	REACT_118567 (Reactome)
	p-T,4S-IRF3:p-T,4S-IRF3	Arrow	REACT_147821 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3			REACT_118567 (Reactome)
p-T,4S-IRF3:p-T,4S-IRF3			REACT_163902 (Reactome)
viral dsRNA:TLR3:TRIF:RIP1		Arrow	REACT_6973 (Reactome)
viral DNA with 3' sticky ends			REACT_163654 (Reactome)
viral dsDNA			REACT_147878 (Reactome)