Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways (Homo sapiens)

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394, 3052519, 4947351324, 5321, 51318, 52172325, 3751, 541, 8, 143532, 35, 446, 9, 151211, 40, 4310, 31272333, 422336, 46, 4845342232352524826nucleoplasmmitochondrial matrixcytosolCASP1(1-404) iE-DAP TAB2 IKBKG SUGT1 TXNIP:NLRP3RIPK2 TRAF6 NLRP3elicitors:NLRP3oligomer:ASCTRAF6 E3/E2ubiquitin ligasecomplexK+TAB2 MDP Phospho-p38 MAPKTXNp-S177,S181-IKBKB PAMP:NODoligomer:K63-polyUb-RIP2:NEMO:TAK1 complexNLRP3:SUGT1:HSP90SiO2 NOD2 p-T180,Y182-MAPK11 IPAFelicitors:NLRC4:Procaspase-1NOD2 Pyrin trimerp-T180,Y182-MAPK13 TAB1 AIM2K63polyUbdsDNA:AIM2 oligomerUb-285-IKBKG p-T184,T187-MAP3K7 NLRP3elicitors:NLRP3oligomer:ASC:Procaspase-1HSP90AB1 iE-DAP CASP2(2-452) Alpha-hemolysin TAB2 CARD9NLRC4 NOD1 CASP8(1-479) K63polyUb Ub-209-RIPK2 AIM2 ATP TAB1 dsDNA:AIM2 oligomer p-T183,Y185-MAPK12 TAB3 TAB3 ITCH BIRC2 TAB3 MDP:NLRP1NOD2 TAK1 complexUb-209-RIPK2 APP(672-711) MAP3K7 ATP:P2X7oligomer:Pannexin-1NOD2 iE-DAP ATP PYCARD SUGT1 P2RX7 SiO2 UBE2N MEFV RIP2 ubiquitinligasesNOD1 prgJ prgJ PANX1 HSP90AB1 IKBKG TAB2 p-2S,S376,T,T209,T387-IRAK1 Double-stranded DNACASP1(1-404) PAMP:NODoligomer:RIP2:NEMO2xHC-TXNiE-DAP PAMP:NODoligomer:RIP2:CARD9NLRP3 iE-DAP MAP2K6ATP:P2X7 oligomerHSP90AB1 TAK1 complexNLRP1 BCL2 Bcl-2/Bcl-X(L):NLRP1MAPK11 TAB2 p-S207,T211-MAP2K6NLRP3 elicitor smallmoleculesATPUb-209-RIPK2 CASP9(1-416) MAP3K7 Flagellin TAB1 NOD2 NOD1:iE-DAPMDP K63polyUb ATP:P2X7NOD1 NOD1 NLRP3 PSTPIP1 trimer:PyrintrimerNOD2 P2RX7 NOD1 TAB3 MDP Long prodomaincaspasesIKBKG PYCARD NOD2 p-T180,Y182-MAPK14 TXNIP IKBKG HSP90AB1 SUGT1 MDP MAP3K7 TNFAIP3NLRP3 elicitorproteins:NLRP3NFKB2(1-454) UBE2V1 PSTPIP1 NLRP3 PSTPIP1 CARD9 IKBKG IPAF elicitors:NLRC4K63polyUb ATPIKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBdsDNA:AIM2 oligomer NOD1 SiO2 TAB1 PAMP:NODoligomer:K63-polyUb-RIP2:NEMONOD1 NLRP1 CHUK:IKBKB:IKBKGiE-DAP PYCARDCHUK SUGT1:HSP90NLRP3 NLRC4NOD2 PYCARD NLRP1NOD1 dsDNA:AIM2MEFV MAP3K7 RELA Alpha-hemolysin P2RX7 CASP1(1-404) UBE2V1 2xHC-TXN Flagellin MDPNOD2NLRP1 TXNIP iE-DAPOxidizedthioredoxin:TXNIPIKBKGNOD2 RIPK2 Asb NLRP3elicitors:NLRP3TAB1 Asb K63polyUb-TRAF6 RIPK2 BCL2L1 Pyrin trimer:ASCPAMP:NODoligomer:RIP2CASP1(1-404) NFKB1(1-433) IKBKG ROSPSTPIP1 trimerMAPK14 P2RX7MDP TAB3 ATP MAPK12 Alpha-hemolysin K63polyUb CASP8(1-479) Ub-209-RIPK2 iE-DAP HUA TXN p38 MAPKBCL2L1 NOD2 APP(672-711) ATPADPMDP:NLRP1:ATPoligomerAPP(672-711) iE-DAP PANX1ADPCASP4(?-377) HSP90AB1NLRP3Bcl-2/Bcl-X(L)prgJ NLRP3elicitors:NLRP3oligomerNOD1 p-IRAK2 TXNIP MDP:NLRP1:ATPMDP CYLDdsDNA:AIM2oligomer:ASCMDP:NOD2ATP Asb MDP NOD1 MAP3K7 MDP:NOD2 oligomerMDP CASP2(2-452) IKBKG PYCARD SUGT1 NLRP3 elicitorproteinsSUGT1RIPK2 ATPMDP Activated TAKcomplexesNOD1 MEFV UBE2V1 TXNIPDouble-stranded DNA BCL2 MDP CASP4(?-377) NOD1 HUA iE-DAP PAMP:NODoligomer:RIP2:K63-pUb-K285-NEMOUBE2N HUA TRAF6 Flagellin CASP1(1-404)MDP CASP9(1-416) IPAF elicitorsNFkB ComplexIKBKB NOD1NOD2 iE-DAP UBE2N K63polyUb NLRP3 genePAMP:NOD oligomerNOD1:iE-DAP oligomerMDP p-S176,S180-CHUK BIRC3 RIPK2NLRC4 PYCARD iE-DAP NLRP3 elicitors:NLRP3 oligomer NLRP3 elicitor smallmolecules:NLRP3dsDNA:AIM2oligomer:ASC:Procaspase-1K+PAMP:NODoligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complexNLRP3 elicitors:NLRP3 oligomer iE-DAP MDP MAPK13 NOD1:iE-DAP:Longprodomain caspasesNLRP3 Thioredoxin:TXNIPCASP1(1-404) 48, 5020, 28, 292, 387, 20, 28, 29162, 38, 41


Description

The innate immune system is the first line of defense against invading microorganisms, a broad specificity response characterized by the recruitment and activation of phagocytes and the release of anti-bacterial peptides. The receptors involved recognize conserved molecules present in microbes called pathogen-associated molecular patterns (PAMPs), and/or molecules that are produced as a result of tissue injury, the damage associated molecular pattern molecules (DAMPs). PAMPs are essential to the pathogen and therefore unlikely to vary. Examples are lipopolysaccharide (LPS), peptidoglycans (PGNs) and viral RNA. DAMPs include intracellular proteins, such as heat-shock proteins and extracellular matrix proteins released by tissue injury, such as hyaluronan fragments. Non-protein DAMPs include ATP, uric acid, heparin sulfate and dsDNA. The receptors for these factors are referred to collectively as pathogen- or pattern-recognition receptors (PRRs). The best studied of these are the membrane-associated Toll-like receptor family. Less well studied but more numerous are the intracellular nucleotide-binding domain, leucine rich repeat containing receptors (NLRs) also called nucleotide binding oligomerization domain (NOD)-like receptors, a family with over 20 members in humans and over 30 in mice. These recognise PAMPs/DAMPs from phagocytosed microorganisms or from intracellular infections (Kobayashi et al. 2003, Proell et al. 2008, Wilmanski et al. 2008). Some NLRs are involved in process unrelated to pathogen detection such as tissue homeostasis, apoptosis, graft-versus-host disease and early development (Kufer & Sansonetti 2011).


Structurally NLRs can be subdivided into the caspase-recruitment domain (CARD)-containing NLRCs (NODs) and the pyrin domain (PYD)-containing NLRPs (NALPs), plus outliers including ice protease (caspase-1) activating factor (IPAF) (Martinon & Tschopp, 2005). In practical terms, NLRs can be divided into the relatively well characterized NOD1/2 which signal via RIP2 primarily to NFkappaB, and the remainder, some of which participate in macromolecular structures called Inflammasomes that activate caspases. Mutations in several members of the NLR protein family have been linked to inflammatory diseases, suggesting these molecules play important roles in maintaining host-pathogen interactions and inflammatory responses.


Most NLRs have a tripartite structure consisting of a variable amino-terminal domain, a central nucleotide-binding oligomerization domain (NOD or NACHT) that is believed to mediate the formation of self oligomers, and a carboxy-terminal leucine-rich repeat (LRR) that detects PAMPs/DAMPs. In most cases the amino-terminal domain includes protein-interaction modules, such as CARD or PYD, some harbour baculovirus inhibitor repeat (BIR) or other domains. For most characterised NLRs these domains have been attributed to downstream signaling

Under resting conditions, NLRs are thought to be present in an autorepressed form, with the LRR folded back onto the NACHT domain preventing oligomerization. Accessory proteins may help maintain the inactive state. PAMP/DAMP exposure is thought to triggers conformational changes that expose the NACHT domain enabling oligomerization and recruitment of effectors, though it should be noted that due to the lack of availability of structural data, the mechanistic details of NLR activation remain largely elusive.

New terminology for NOD-like receptors was adopted by the Human Genome Organization (HUGO) in 2008 to standardize the nomenclature of NLRs. The acronym NLR, once standing for NOD-like receptor, now is an abbreviation of 'nucleotide-binding domain, leucine-rich repeat containing' protein. The term NOD-like receptor is officially outdated and replaced by NLRC where the C refers to the CARD domain. However the official gene symbols for NOD1 and NOD2 still contain NOD and this general term is still widely used. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 168643
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Jupe, Steve

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101553view11:41, 1 November 2018ReactomeTeamreactome version 66
101089view21:25, 31 October 2018ReactomeTeamreactome version 65
100618view19:59, 31 October 2018ReactomeTeamreactome version 64
100169view16:44, 31 October 2018ReactomeTeamreactome version 63
99719view15:11, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93893view13:43, 16 August 2017ReactomeTeamreactome version 61
93466view11:24, 9 August 2017ReactomeTeamreactome version 61
88079view09:06, 26 July 2016RyanmillerOntology Term : 'signaling pathway in the innate immune response' added !
88078view09:04, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86559view09:21, 11 July 2016ReactomeTeamreactome version 56
83380view11:04, 18 November 2015ReactomeTeamVersion54
81556view13:05, 21 August 2015ReactomeTeamVersion53
77025view08:32, 17 July 2014ReactomeTeamFixed remaining interactions
76730view12:09, 16 July 2014ReactomeTeamFixed remaining interactions
76055view10:11, 11 June 2014ReactomeTeamRe-fixing comment source
75765view11:27, 10 June 2014ReactomeTeamReactome 48 Update
75115view14:06, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74865view14:18, 3 May 2014EgonwMarked a metabolite as a DataNode type="Metabolite"...
74762view08:50, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2xHC-TXN ProteinP10599 (Uniprot-TrEMBL)
2xHC-TXNProteinP10599 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AIM2 ProteinO14862 (Uniprot-TrEMBL)
AIM2ProteinO14862 (Uniprot-TrEMBL)
APP(672-711) ProteinP05067 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATP:P2X7 oligomer:Pannexin-1ComplexR-HSA-877242 (Reactome)
ATP:P2X7 oligomerComplexR-HSA-877257 (Reactome)
ATP:P2X7ComplexR-HSA-877166 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated TAK complexesComplexR-HSA-772536 (Reactome)
Alpha-hemolysin ProteinP09616 (Uniprot-TrEMBL)
Asb MetaboliteCHEBI:46661 (ChEBI)
BCL2 ProteinP10415 (Uniprot-TrEMBL)
BCL2L1 ProteinQ07817 (Uniprot-TrEMBL)
BIRC2 ProteinQ13490 (Uniprot-TrEMBL)
BIRC3 ProteinQ13489 (Uniprot-TrEMBL)
Bcl-2/Bcl-X(L):NLRP1ComplexR-HSA-879218 (Reactome)
Bcl-2/Bcl-X(L)ComplexR-HSA-879209 (Reactome)
CARD9 ProteinQ9H257 (Uniprot-TrEMBL)
CARD9ProteinQ9H257 (Uniprot-TrEMBL)
CASP1(1-404) ProteinP29466 (Uniprot-TrEMBL)
CASP1(1-404)ProteinP29466 (Uniprot-TrEMBL)
CASP2(2-452) ProteinP42575 (Uniprot-TrEMBL)
CASP4(?-377) ProteinP49662 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP9(1-416) ProteinP55211 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
CYLDProteinQ9NQC7 (Uniprot-TrEMBL)
Double-stranded DNA MetaboliteCHEBI:16991 (ChEBI)
Double-stranded DNAMetaboliteCHEBI:16991 (ChEBI)
Flagellin R-STY-874031 (Reactome)
HSP90AB1 ProteinP08238 (Uniprot-TrEMBL)
HSP90AB1ProteinP08238 (Uniprot-TrEMBL)
HUA MetaboliteCHEBI:16336 (ChEBI)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBComplexR-HSA-177663 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
IKBKGProteinQ9Y6K9 (Uniprot-TrEMBL)
IPAF elicitors:NLRC4:Procaspase-1ComplexR-HSA-874083 (Reactome)
IPAF elicitors:NLRC4ComplexR-HSA-877394 (Reactome)
IPAF elicitorsComplexR-STY-1252386 (Reactome)
ITCH ProteinQ96J02 (Uniprot-TrEMBL)
K+MetaboliteCHEBI:29103 (ChEBI)
K63polyUb R-HSA-450152 (Reactome)
K63polyUb-TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
Long prodomain caspasesComplexR-HSA-622416 (Reactome)
MAP2K6ProteinP52564 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
MAPK12 ProteinP53778 (Uniprot-TrEMBL)
MAPK13 ProteinO15264 (Uniprot-TrEMBL)
MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
MDP MetaboliteCHEBI:59414 (ChEBI)
MDP:NLRP1:ATP oligomerR-HSA-1296412 (Reactome)
MDP:NLRP1:ATPComplexR-HSA-879207 (Reactome)
MDP:NLRP1ComplexR-HSA-877370 (Reactome)
MDP:NOD2 oligomerComplexR-HSA-708350 (Reactome)
MDP:NOD2ComplexR-HSA-168414 (Reactome)
MDPMetaboliteCHEBI:59414 (ChEBI)
MEFV ProteinO15553 (Uniprot-TrEMBL)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKB2(1-454) ProteinQ00653 (Uniprot-TrEMBL)
NFkB ComplexComplexR-HSA-177673 (Reactome)
NLRC4 ProteinQ9NPP4 (Uniprot-TrEMBL)
NLRC4ProteinQ9NPP4 (Uniprot-TrEMBL)
NLRP1 ProteinQ9C000 (Uniprot-TrEMBL)
NLRP1ProteinQ9C000 (Uniprot-TrEMBL)
NLRP3

elicitors:NLRP3

oligomer:ASC:Procaspase-1
ComplexR-HSA-925458 (Reactome)
NLRP3

elicitors:NLRP3

oligomer:ASC
ComplexR-HSA-877381 (Reactome)
NLRP3

elicitors:NLRP3

oligomer
R-NUL-1296409 (Reactome)
NLRP3 elicitors:NLRP3ComplexR-HSA-1306878 (Reactome)
NLRP3 ProteinQ96P20 (Uniprot-TrEMBL)
NLRP3 elicitor proteins:NLRP3ComplexR-HSA-1306879 (Reactome)
NLRP3 elicitor proteinsComplexR-NUL-9038383 (Reactome) Several intact viruses, fungi and bacteria can induce NLRP3 activation, as can human proteins such as beta-amyloid (Schroder & Tschopp 2010).
NLRP3 elicitor small molecules:NLRP3ComplexR-HSA-877226 (Reactome)
NLRP3 elicitor small moleculesComplexR-ALL-877245 (Reactome) Several intact viruses, fungi and bacteria can induce NLRP3 activation, as can human proteins such as beta-amyloid (Schroder & Tschopp 2010).
NLRP3 elicitors:NLRP3 oligomer R-NUL-1296409 (Reactome)
NLRP3 geneGeneProductENSG00000162711 (Ensembl)
NLRP3:SUGT1:HSP90ComplexR-HSA-874086 (Reactome)
NLRP3ProteinQ96P20 (Uniprot-TrEMBL)
NOD1 ProteinQ9Y239 (Uniprot-TrEMBL)
NOD1:iE-DAP oligomerComplexR-HSA-622306 (Reactome)
NOD1:iE-DAP:Long prodomain caspasesComplexR-HSA-622417 (Reactome)
NOD1:iE-DAPComplexR-HSA-168408 (Reactome)
NOD1ProteinQ9Y239 (Uniprot-TrEMBL)
NOD2 ProteinQ9HC29 (Uniprot-TrEMBL)
NOD2ProteinQ9HC29 (Uniprot-TrEMBL)
Oxidized thioredoxin:TXNIPComplexR-HSA-1250249 (Reactome)
P2RX7 ProteinQ99572 (Uniprot-TrEMBL)
P2RX7ProteinQ99572 (Uniprot-TrEMBL)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complexComplexR-HSA-706478 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complexComplexR-HSA-706477 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMOComplexR-HSA-706480 (Reactome)
PAMP:NOD oligomer:RIP2:CARD9ComplexR-HSA-741403 (Reactome)
PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMOComplexR-HSA-741418 (Reactome)
PAMP:NOD oligomer:RIP2:NEMOComplexR-HSA-688994 (Reactome)
PAMP:NOD oligomer:RIP2ComplexR-HSA-168409 (Reactome)
PAMP:NOD oligomerComplexR-HSA-708346 (Reactome)
PANX1 ProteinQ96RD7 (Uniprot-TrEMBL)
PANX1ProteinQ96RD7 (Uniprot-TrEMBL)
PSTPIP1 ProteinO43586 (Uniprot-TrEMBL)
PSTPIP1 trimer:Pyrin trimerComplexR-HSA-879197 (Reactome)
PSTPIP1 trimerComplexR-HSA-879213 (Reactome)
PYCARD ProteinQ9ULZ3 (Uniprot-TrEMBL)
PYCARDProteinQ9ULZ3 (Uniprot-TrEMBL)
Phospho-p38 MAPKComplexR-HSA-1250100 (Reactome)
Pyrin trimer:ASCComplexR-HSA-877352 (Reactome)
Pyrin trimerComplexR-HSA-879202 (Reactome)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RIP2 ubiquitin ligasesComplexR-HSA-1248659 (Reactome)
RIPK2 ProteinO43353 (Uniprot-TrEMBL)
RIPK2ProteinO43353 (Uniprot-TrEMBL)
ROSMetaboliteCHEBI:26523 (ChEBI)
SUGT1 ProteinQ9Y2Z0 (Uniprot-TrEMBL)
SUGT1:HSP90ComplexR-HSA-874112 (Reactome)
SUGT1ProteinQ9Y2Z0 (Uniprot-TrEMBL)
SiO2 MetaboliteCHEBI:30563 (ChEBI)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 complexComplexR-HSA-446878 (Reactome)
TAK1 complexComplexR-HSA-8947970 (Reactome)
TNFAIP3ProteinP21580 (Uniprot-TrEMBL)
TRAF6 E3/E2

ubiquitin ligase

complex
ComplexR-HSA-1248657 (Reactome)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TXN ProteinP10599 (Uniprot-TrEMBL)
TXNIP ProteinQ9H3M7 (Uniprot-TrEMBL)
TXNIP:NLRP3ComplexR-HSA-1250285 (Reactome)
TXNIPProteinQ9H3M7 (Uniprot-TrEMBL)
TXNProteinP10599 (Uniprot-TrEMBL)
Thioredoxin:TXNIPComplexR-HSA-1250277 (Reactome)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-209-RIPK2 ProteinO43353 (Uniprot-TrEMBL)
Ub-285-IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
dsDNA:AIM2 oligomer:ASC:Procaspase-1ComplexR-HSA-874100 (Reactome)
dsDNA:AIM2 oligomer:ASCComplexR-HSA-874098 (Reactome)
dsDNA:AIM2 oligomer R-HSA-1296424 (Reactome)
dsDNA:AIM2 oligomerR-HSA-1296424 (Reactome)
dsDNA:AIM2ComplexR-HSA-874096 (Reactome)
iE-DAP MetaboliteCHEBI:59271 (ChEBI)
iE-DAPMetaboliteCHEBI:59271 (ChEBI)
p-2S,S376,T,T209,T387-IRAK1 ProteinP51617 (Uniprot-TrEMBL) This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).
p-IRAK2 ProteinO43187 (Uniprot-TrEMBL)
p-S176,S180-CHUK ProteinO15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6ProteinP52564 (Uniprot-TrEMBL)
p-T180,Y182-MAPK11 ProteinQ15759 (Uniprot-TrEMBL)
p-T180,Y182-MAPK13 ProteinO15264 (Uniprot-TrEMBL)
p-T180,Y182-MAPK14 ProteinQ16539 (Uniprot-TrEMBL)
p-T183,Y185-MAPK12 ProteinP53778 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p38 MAPKComplexR-HSA-1250102 (Reactome)
prgJ ProteinP41785 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2xHC-TXNArrowR-HSA-1250253 (Reactome)
2xHC-TXNArrowR-HSA-1250280 (Reactome)
ADPArrowR-HSA-1247960 (Reactome)
ADPArrowR-HSA-168184 (Reactome)
ADPArrowR-HSA-727819 (Reactome)
AIM2R-HSA-844619 (Reactome)
ATP:P2X7 oligomer:Pannexin-1ArrowR-HSA-877198 (Reactome)
ATP:P2X7 oligomerArrowR-HSA-877158 (Reactome)
ATP:P2X7 oligomerR-HSA-877198 (Reactome)
ATP:P2X7 oligomermim-catalysisR-HSA-877187 (Reactome)
ATP:P2X7ArrowR-HSA-877178 (Reactome)
ATP:P2X7R-HSA-877158 (Reactome)
ATPR-HSA-1247960 (Reactome)
ATPR-HSA-168184 (Reactome)
ATPR-HSA-727819 (Reactome)
ATPR-HSA-877178 (Reactome)
ATPR-HSA-879222 (Reactome)
Activated TAK complexesmim-catalysisR-HSA-168184 (Reactome)
Bcl-2/Bcl-X(L):NLRP1ArrowR-HSA-879201 (Reactome)
Bcl-2/Bcl-X(L)R-HSA-879201 (Reactome)
CARD9R-HSA-741395 (Reactome)
CASP1(1-404)R-HSA-844612 (Reactome)
CASP1(1-404)R-HSA-844617 (Reactome)
CASP1(1-404)R-HSA-844618 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-168184 (Reactome)
CYLDmim-catalysisR-HSA-741411 (Reactome)
Double-stranded DNAR-HSA-844619 (Reactome)
HSP90AB1R-HSA-874087 (Reactome)
IKBKG:p-S176,S180-CHUK:p-S177,S181-IKBKBArrowR-HSA-168184 (Reactome)
IKBKGR-HSA-622415 (Reactome)
IPAF elicitors:NLRC4:Procaspase-1ArrowR-HSA-844617 (Reactome)
IPAF elicitors:NLRC4ArrowR-HSA-874084 (Reactome)
IPAF elicitors:NLRC4R-HSA-844617 (Reactome)
IPAF elicitorsR-HSA-874084 (Reactome)
K+ArrowR-HSA-877187 (Reactome)
K+R-HSA-877187 (Reactome)
K63polyUbArrowR-HSA-688136 (Reactome)
K63polyUbArrowR-HSA-741411 (Reactome)
K63polyUbR-HSA-688137 (Reactome)
K63polyUbR-HSA-741386 (Reactome)
Long prodomain caspasesR-HSA-622420 (Reactome)
MAP2K6R-HSA-727819 (Reactome)
MDP:NLRP1:ATP oligomerArrowR-HSA-844438 (Reactome)
MDP:NLRP1:ATPArrowR-HSA-879222 (Reactome)
MDP:NLRP1:ATPR-HSA-844438 (Reactome)
MDP:NLRP1ArrowR-HSA-844447 (Reactome)
MDP:NLRP1R-HSA-879222 (Reactome)
MDP:NOD2 oligomerArrowR-HSA-708349 (Reactome)
MDP:NOD2ArrowR-HSA-168412 (Reactome)
MDP:NOD2R-HSA-708349 (Reactome)
MDPR-HSA-168412 (Reactome)
MDPR-HSA-844447 (Reactome)
NFkB ComplexArrowR-HSA-9603905 (Reactome)
NLRC4R-HSA-874084 (Reactome)
NLRP1R-HSA-844447 (Reactome)
NLRP1R-HSA-879201 (Reactome)
NLRP3

elicitors:NLRP3

oligomer:ASC:Procaspase-1
ArrowR-HSA-844612 (Reactome)
NLRP3

elicitors:NLRP3

oligomer:ASC
ArrowR-HSA-844610 (Reactome)
NLRP3

elicitors:NLRP3

oligomer:ASC
R-HSA-844612 (Reactome)
NLRP3

elicitors:NLRP3

oligomer
ArrowR-HSA-1296421 (Reactome)
NLRP3

elicitors:NLRP3

oligomer
R-HSA-844610 (Reactome)
NLRP3 elicitors:NLRP3R-HSA-1296421 (Reactome)
NLRP3 elicitor proteins:NLRP3ArrowR-HSA-844440 (Reactome)
NLRP3 elicitor proteinsR-HSA-844440 (Reactome)
NLRP3 elicitor small molecules:NLRP3ArrowR-HSA-1306876 (Reactome)
NLRP3 elicitor small moleculesR-HSA-1306876 (Reactome)
NLRP3 geneR-HSA-9603905 (Reactome)
NLRP3:SUGT1:HSP90ArrowR-HSA-873951 (Reactome)
NLRP3:SUGT1:HSP90R-HSA-1306876 (Reactome)
NLRP3:SUGT1:HSP90R-HSA-844440 (Reactome)
NLRP3ArrowR-HSA-9603905 (Reactome)
NLRP3R-HSA-1250272 (Reactome)
NLRP3R-HSA-873951 (Reactome)
NOD1:iE-DAP oligomerArrowR-HSA-622310 (Reactome)
NOD1:iE-DAP:Long prodomain caspasesArrowR-HSA-622420 (Reactome)
NOD1:iE-DAPArrowR-HSA-168400 (Reactome)
NOD1:iE-DAPR-HSA-622310 (Reactome)
NOD1:iE-DAPR-HSA-622420 (Reactome)
NOD1R-HSA-168400 (Reactome)
NOD2R-HSA-168412 (Reactome)
Oxidized thioredoxin:TXNIPR-HSA-1250253 (Reactome)
P2RX7R-HSA-877178 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complexArrowR-HSA-688985 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:TAK1 complexR-HSA-706479 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complexArrowR-HSA-706479 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMOArrowR-HSA-688137 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMOR-HSA-688136 (Reactome)
PAMP:NOD oligomer:K63-polyUb-RIP2:NEMOR-HSA-688985 (Reactome)
PAMP:NOD oligomer:RIP2:CARD9ArrowR-HSA-741395 (Reactome)
PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMOArrowR-HSA-741386 (Reactome)
PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMOR-HSA-741411 (Reactome)
PAMP:NOD oligomer:RIP2:NEMOArrowR-HSA-622415 (Reactome)
PAMP:NOD oligomer:RIP2:NEMOArrowR-HSA-688136 (Reactome)
PAMP:NOD oligomer:RIP2:NEMOArrowR-HSA-741411 (Reactome)
PAMP:NOD oligomer:RIP2:NEMOR-HSA-688137 (Reactome)
PAMP:NOD oligomer:RIP2:NEMOR-HSA-741386 (Reactome)
PAMP:NOD oligomer:RIP2ArrowR-HSA-168405 (Reactome)
PAMP:NOD oligomer:RIP2R-HSA-622415 (Reactome)
PAMP:NOD oligomer:RIP2R-HSA-741395 (Reactome)
PAMP:NOD oligomerR-HSA-168405 (Reactome)
PANX1R-HSA-877198 (Reactome)
PSTPIP1 trimer:Pyrin trimerArrowR-HSA-879221 (Reactome)
PSTPIP1 trimerR-HSA-879221 (Reactome)
PYCARDR-HSA-844610 (Reactome)
PYCARDR-HSA-844620 (Reactome)
PYCARDR-HSA-877361 (Reactome)
Phospho-p38 MAPKArrowR-HSA-1247960 (Reactome)
Pyrin trimer:ASCArrowR-HSA-877361 (Reactome)
Pyrin trimerR-HSA-877361 (Reactome)
Pyrin trimerR-HSA-879221 (Reactome)
R-HSA-1247960 (Reactome) p38 MAPK has 4 representative isoforms in humans, p38 alpha (Han et al. 1993), p38-beta (Jiang et al. 1996), p38-gamma (Lechner et al. 1996) and p38-delta (Hu et al. 1999). All are activated by phosphorylation on a canonical TxY motif by the dual-specificity kinase MKK6, which displays minimal substrate selectivity amongst the p38 isoforms (Zarubin & Han, 2005). p38 alpha and gamma are also activated by MKK3.
R-HSA-1250253 (Reactome) ROS induce the dissociation of TXNIP from thioredoxin, freeing TXNIP to subsequently bind NLRP3 and bring about activation of the NLRP3 inflammasome (Zhou et al. 2010).
R-HSA-1250264 (Reactome) TXNIP interacts with the redox-active domain of thioredoxin (TRX) and is believed to act as an oxidative stress mediator by inhibiting TRX activity or by limiting its bioavailability (Nishiyama et al. 1999, Liyanage et al. 2007).
R-HSA-1250272 (Reactome) Thioredoxin-interacting protein (TXNIP) binds NLRP3. Reactive oxygen species (ROS) such as H2O2 increase this interaction, while the ROS inhibitor APDC blocks it (Zhou et al. 2010). This interaction is proposed to activate the NLRP3 inflammasome.
R-HSA-1250280 (Reactome) The presence of reactive oxygen species (ROS) leads to the oxidation of thioredoxin and consequent release of TXNIP (Zhou et al. 2010). The source of the ROS is unclear but they are known to be essential for caspase-1 activation (Cruz et al. 2007) and are produced in response to all known NLRP3 activators (Dostert et al. 2008, Zhou et al. 2010). The freed TXNIP binds NLRP3 and is proposed to activate the NLRP3 inflammasome, explaining how ROS can bring about NLRP3 activation.
R-HSA-1296421 (Reactome) NLRP3 contains a NACHT/NOD domain that in related proteins is responsible for oligomerization (Inohara & Nunez 2001, 2003). NLRP1 forms oligomers upon stimulation with MDP (Faustin et al. 2007) and the enforced oligomerization of NLRP3 PYD domains enhances ASC-dependent effects on apoptosis (Dowds et al. 2002). NOD-mediated oligomerization is widely considered to be part of the activation process for the NLRP3 inflammasome (Schroder et al. 2010, Schroder & Tschopp, 2010). The extent of oligomerization is not known, but models based on the the apoptotic initiator protein Apaf-1 suggest a posible heptameric platform (Proell et al. 2008).
R-HSA-1306876 (Reactome) The NLRP3 inflammasome is activated by a range of stimuli of microbial, endogenous and exogenous origins including several viruses, bacterial pore forming toxins (e.g. Craven et al. 2009), and various irritants that form crystalline or particulate structures (see Cassel et al. 2009). Multiple studies have shown that phagocytosis of particulate elicitors is necessary for activation (e.g. Hornung et al. 2008) but not for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006), which is also involved in the response to nigericin and maitotoxin (Pellegrin & Suprenenant 2007). Direct binding of elicitors to NLRP3 has not been demonstrated and the exact process of activation is unclear, though speculated to involve changes in conformation that make available the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003).

Three overlapping mechanisms are believed to be involved in NLRP3 activation. ATP stimulates the P2X7 ATP-gated ion channel leading to K+ efflux which appears necessary for NLRP3 inflammasome activation (Kahlenberg & Dubyak 2004, Dostert et al. 2008), and is believed to induce formation of pannexin-1 membrane pores. These pores give direct access of NLPR3 agonists to the cytosol. A second mechanism is the endocytosis of crystalline or particulate structures, leading to damaged lysosomes which release their contents (Hornung et al. 2008, Halle et al. 2008). The third element is the generation of reactive oxygen species (ROS) which activate NLRP3, shown to be a critical step for the activation of caspase-1 following ATP stimulation (Cruz et al. 2007). The source of the ROS is unclear.
R-HSA-168184 (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.

R-HSA-168400 (Reactome) Early studies suggested that NOD1 and NOD2 responded to lipopolysaccharides (LPS), but this was later shown to be due to contamination of LPS with bacterial peptidoglycans (PGNs), the true elicitor for NODs. It is generally believed that PGNs bind NOD1 though this remains to be formally demonstrated. NOD1 senses PGN moieties with a minimal dipeptide structure of D-gamma-glutamyl-meso-diaminopimelic acid (iE-DAP), which is unique to PGN structures from all Gram-negative bacteria and certain Gram-positive bacteria, including the genus Listeria and Bacillus. Attachment of acyl residues enhances NOD1 stimulation several hundred fold, possibly by facilitating PGN entry into the cell (Hasegawa et al. 2007).
R-HSA-168405 (Reactome) NOD1 and NOD2 (NOD) interact with the inflammatory kinase RIP2 (RICK) via a homophilic association between CARD domains (Inohara et al. 1999, Ogura et al. 2001). This has the effect of bringing several RIP2 molecules into close proximity, enhancing RIP2-RIP2 interactions (Inohara et al. 2000), a key step in what is termed the 'Induced Proximity Model' for NOD activation of NFkappaB. Note that though the interaction of every NOD with RIP2 is implied here this may not be required for RIP2 activation. RIP2 recruitment leads to subsequent activation of NFkappaB. The kinase activity of RIP2 was initially described as not required (Inohara et al. 2000) but subsequently suggested to be involved in determining signal strength (Windheim et al. 2007) and recently found to be essential for maintaining RIP2 stability and it's role in mediating NOD signaling (Nembrini et al. 2009).
R-HSA-168412 (Reactome) Muramyl dipeptide (MDP) is an essential structural component of bacterial peptidoglycan (PGN) and the minimal elicitor recognized by NOD2. As MDP is present in nearly all bacteria NOD2 is a general sensor of bacteria. NOD2 has additionally been reported to respond to ssRNA (Sabbah et al. 2009) and play a role in T cell activation (Shaw et al. 2011).
R-HSA-622310 (Reactome) NOD1 is activated by iE-DAP in a LRR domain dependent manner. The LRR domain has a negative influence on NOD1 self-association (Inohara et al. 2000); binding of iE-DAP likely causes conformational changes that free the NACHT domain, allowing oligomerization and subsequent association of other proteins. Coimmunoprecipitation experiments demonstrate that NOD1 can interact with itself (Inohara et al. 1999) via the NACHT domain (Inohara et al. 2000). NACHT domains are part of the AAA+ domain family. Members of this family form hexamers or heptamers. Based on this observation, NOD1 and NOD2 are believed to form oligomers of this size (Martinon & Tschopp, 2005).
R-HSA-622415 (Reactome) An intermediate region located between the CARD and kinase domains mediates the interaction of RIP2 with the IKK complex regulatory subunit NEMO. This interaction is presumed to link NOD1:RIP2 to the IKK complex, ultimately leading to the phosphorylation of IkappaB-alpha and the activation of NF-kappaB (Inohara et al. 2000). Although every NOD molecule in the oligomeric complex is represented as binding RIP2, binding to every member of the complex may not be required for subsequent signaling events.
R-HSA-622420 (Reactome)