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

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23341693624, 264, 12, 2135, 431822, 30, 47212534937, 4840933, 5129, 4926, 38, 42318, 10, 1119, 4345307, 15143, 27, 28342195, 341712mitochondrial matrixcytosolSUGT1 CYLDIKBKG IPAF elicitors:NLRC4MAPK13 UBE2V1 p-S207,T211-MAP2K6HUA MDP:NLRP1:ATPiE-DAP ATPNOD1 ITCH IKBKG MAPK11 NLRP3 K+K+Double-stranded DNATAB3 NOD2 UBE2N 2xHC-TXNiE-DAP Ub-209-RIPK2 TAB3 TAB1 MDP:NOD2HUA UBE2V1 Ub-209-RIPK2 PYCARDMDP PAMP:NODoligomer:K63-polyUb-RIP2:NEMOHSP90AB1 Bcl-2/Bcl-X(L)NLRP3elicitors:NLRP3oligomerOxidizedthioredoxin:TXNIPMDP ATP NLRP3elicitors:NLRP3oligomer:ASCSiO2 ATP PANX1 NOD2 TAB2 IKBKGCASP4(?-377) SUGT1ATPMDP:NLRP1TXNIP:NLRP3K63polyUbNLRP1 APP(672-711) P2RX7 AIM2 NOD1 p38 MAPKTAB3 UBE2N Ub-209-RIPK2 PSTPIP1 CASP8(1-479) TRAF6 HSP90AB1MAP3K7 NOD1:iE-DAP:Longprodomain caspasesMAPK12 NOD2 MDP APP(672-711) iE-DAP iE-DAP NLRP3 IKBKG SUGT1 TAB1 Thioredoxin:TXNIPTRAF6 PYCARD TAB2 NOD2NLRP3K63polyUb p-T180,Y182-MAPK11 TAB2 CASP2(2-452) MEFV MDP MAP3K7 Asb K63polyUb MDP NOD1 NOD1 SiO2 ATP Flagellin Pyrin trimer:ASCNLRP3 BCL2 ATPNOD1 MDP MAP3K7 NLRP3 K63polyUb P2RX7ROSiE-DAP NOD1 NOD1 TXN dsDNA:AIM2oligomer:ASC:Procaspase-1BIRC2 NLRP3 elicitorproteinsMDP p-S176,S180-IKKA iE-DAP CASP1(1-404) ATP:P2X7oligomer:Pannexin-1CASP1(1-404) NOD1 ATP MEFV CASP4(?-377) p-S177,S181-IKBKB CASP9(1-416) ATP:P2X7TXNIP SiO2 iE-DAP MAPK14 K63polyUb NOD2 MAP3K7 dsDNA:AIM2oligomer:ASCNLRC4 p-T180,Y182-MAPK14 PAMP:NODoligomer:RIP2:NEMOIKBKG RIPK2TNFAIP3NLRP1 P2RX7 MDP RIPK2 UBE2V1 SUGT1 TXNIP2xHC-TXN MDP prgJ TAB2 TAB1 MDP NOD1 NLRC4 K63polyUb-TRAF6 Asb dsDNA:AIM2 oligomer p-T183,Y185-MAPK12 IKBKG PSTPIP1 trimer:PyrintrimerMDP iE-DAP TXNIP CHUK PANX1PAMP:NODoligomer:RIP2:K63-pUb-K285-NEMONOD2 CASP2(2-452) Ub-285-IKBKG TAB3 ADPMDP:NOD2 oligomerIPAFelicitors:NLRC4:Procaspase-1NLRP1NLRP1 NLRP3 elicitors:NLRP3 oligomer PYCARD NOD1:iE-DAP oligomerPAMP:NOD oligomerTAB1 MAP3K7 RIPK2 Phospho-p38 MAPKDouble-stranded DNA iE-DAP Long prodomaincaspasesNLRP3elicitors:NLRP3MDP:NLRP1:ATPoligomerNLRP3 elicitor smallmoleculesSUGT1 NOD1 iE-DAP p-T184,T187-MAP3K7 CASP1(1-404) BIRC3 dsDNA:AIM2CASP1(1-404) SUGT1:HSP90iE-DAPNLRC4PAMP:NODoligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complexBCL2 NLRP3 NLRP3 elicitors:NLRP3 oligomer NOD2 Ub-209-RIPK2 IPAF elicitorsCASP1(1-404) Flagellin TAB2 Flagellin Bcl-2/Bcl-X(L):NLRP1ATPTAK1 complexPSTPIP1 TXNNLRP3:SUGT1:HSP90NOD1:iE-DAPdsDNA:AIM2 oligomer IKBKG HSP90AB1 NOD1 PSTPIP1 trimeriE-DAP IKBKB prgJ CASP9(1-416) NLRP3 elicitor smallmolecules:NLRP3NOD2 MDPHUA p-T180,Y182-MAPK13 dsDNA:AIM2 oligomerNOD2 PYCARD NOD1UBE2N PYCARD K63polyUb AIM2Alpha-hemolysin PAMP:NODoligomer:RIP2:CARD9BCL2L1 TAK1 complexAsb RIPK2 MEFV NOD2 TAB3 CHUK:IKBKB:IKBKGNLRP3elicitors:NLRP3oligomer:ASC:Procaspase-1Alpha-hemolysin NOD1 HSP90AB1 Pyrin trimerAlpha-hemolysin NOD2 PYCARD p-2S,S376,T,T209,T387-IRAK1 NOD2 CARD9 prgJ CARD9Activated TAKcomplexesRIP2 ubiquitinligasesTXNIP Activated IKKComplexMDP APP(672-711) p-IRAK2 BCL2L1 PAMP:NODoligomer:RIP2MDP ADPHSP90AB1 ATP:P2X7 oligomerIKBKG P2RX7 RIPK2 iE-DAP CASP8(1-479) TAB1 TRAF6 E3/E2ubiquitin ligasecomplexNLRP3 elicitorproteins:NLRP3PAMP:NODoligomer:K63-polyUb-RIP2:NEMO:TAK1 complexMAP2K6CASP1(1-404)13, 44, 5020, 463913, 41, 44, 5020, 32, 46


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: 61
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 IKK ComplexComplexR-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.
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)
IKBKGProteinQ9Y6K9 (Uniprot-TrEMBL)
IPAF elicitors:NLRC4:Procaspase-1ComplexR-HSA-874083 (Reactome)
IPAF elicitors:NLRC4ComplexR-NUL-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)
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-ALL-1296409 (Reactome)
NLRP3 elicitors:NLRP3ComplexR-HSA-1306878 (Reactome)
NLRP3 ProteinQ96P20 (Uniprot-TrEMBL)
NLRP3 elicitor proteins:NLRP3ComplexR-HSA-1306879 (Reactome)
NLRP3 elicitor proteinsComplexR-HSA-1306880 (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-ALL-1296409 (Reactome)
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)
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-IKKA 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 IKK ComplexArrowR-HSA-168184 (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)
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)
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:SUGT1:HSP90ArrowR-HSA-873951 (Reactome)
NLRP3:SUGT1:HSP90R-HSA-1306876 (Reactome)
NLRP3:SUGT1:HSP90R-HSA-844440 (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) NOD1 was found to coimmunoprecipitate with several procaspases containing long prodomains with CARDs or DEDs, including caspase-1, caspase-2, caspase-4, caspase-8, and caspase-9, but not those with short prodomains like caspase-3 or caspase-7. Deletions of caspase-9 determined that the CARD domain was required for this interaction (Inohara et al. 1999). More recently, NOD1 activation of apoptosis was shown to require the RIP2-dependent activation of caspase-8, this effect being inhibited by CASP8 and FADD-like apoptosis regulator, also called FLICE-inhibitory protein, FLIP or CLARP (da Silva Correia et al. 2007), which is a specific inhibitor of caspase-8 (Irmler et al. 1997).
R-HSA-688136 (Reactome) The deubiquitinase A20 is a negative feedback regulator of inflammatory responses, induced by NFkappaB activation (Krikos et al. 1992) and NOD stimulation (Masumoto et al. 2006). A20 can deubiquitinate RIP2 and restricts NOD2 induced signals (Hitosumatsu et al. 2008).
R-HSA-688137 (Reactome) The close physical proximity of RIP2 proteins that results from NOD oligomerization triggers the conjugation of lysine (K)-63 linked polyubiquitin chains onto RIP2. Ubiquitination at K209 within the kinase domain was required for subsequent NFkappaB signaling (Hasegawa et al. 2008). The identity of the ubiquitin ligase responsible is an open question, with several candidates capable of RIP2 ubiquitination. TRAF6 has been reported as the ubiquitin ligase responsible (Yang et al. 2007) but subsequent reports suggest it is not responsible (see Tao et al. 2009 and Bertrand et al. 2009). Other candidates include the HECT-domain containing E3 ubiquitin ligase ITCH, which is able to K63 ubiquitinate RIP2 (at an undetermined site that is not K209) and is required for optimal NOD2:RIP2-induced p38 and JNK activation, while inhibiting NOD2:RIP2-induced NFkappaB activation (Tao et al. 2009). The Baculoviral IAP repeat-containing proteins (Birc/cIAP) 2 and 3 have also been shown capable of RIP2 ubiquitination and required for NOD2 signaling (Bertrand et al. 2009). It has been suggested that ITCH and a K209 E3 ligase compete for ubiquitination of RIP2, so that a subset of RIP2 becomes ubiquitinated on K209 to stimulate NEMO ubiquitination and subsequent NFkappaB activation while a second subset of RIP2 is polyubiquitinated by ITCH to activate JNK and p38 signaling (Tao et al. 2009).
R-HSA-688985 (Reactome) K63-polyubiquitinated RIP2 is able to recruit the components of the TAK1 complex, which consists of TAK1, TAB1 and TAB2.
R-HSA-706479 (Reactome) The TAK1 complex consists of Transforming growth factor-beta (TGFB)-activated kinase (TAK1) and TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya et al. 1996, Sakurai et al. 2000). TAB1 promotes TAK1 autophosphorylation at the kinase activation lobe, probably through an allosteric mechanism (Brown et al. 2005, Ono et al. 2001). The TAK1 complex is regulated by polyubiquitination. Binding of TAB2 and TAB3 to Lys63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Binding of multiple TAK1 complexes to the same polyubiquitin chain may promote oligomerization of TAK1, facilitating TAK1 autophosphorylation and subsequent activation of its kinase activity (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that lead to TAK1 activation. Another possibility is that TAB2/3 may recruit the IKK complex by binding to ubiquitinated NEMO; polyubiquitin chains may function as a scaffold for higher order signaling complexes that allow interaction between TAK1 and IKK (Kanayama et al. 2004).
R-HSA-708349 (Reactome) NOD2 is activated by MDP in a LRR domain dependent manner. Based on studies of NOD1 activation and structural data from the NLR-related scaffold Apaf-1, the LRR domain is believed to have a negative influence on NOD2 self-association (Inohara et al. 2000, Riedl & Salvesen 2007); binding of MDP is believed to cause 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 these observations, NOD2 is generally believed to form hexamers or heptamers (Martinon & Tschopp, 2005). NOD2 oliogomerization has been observed in NOD2-transfected HEK293T cells (Zhao et al. 2007).
R-HSA-727819 (Reactome) Within the TAK1 complex (TAK1 plus TAB1 and TAB2/3) activated TAK1 phosphorylates IKKB, MAPK kinase 6 (MKK6) and other MAPKs to activate the NFkappaB and MAPK signaling pathways. TAB2 within the TAK1 complex can be linked to polyubiquitinated TRAF6; current models of IL-1 signaling suggest that the TAK1 complex is linked to TRAF6, itself complexed with polyubiquitinated IRAK1 which is linked via NEMO to the IKK complex. The TAK1 complex is also essential for NOD signaling; NOD receptors bind RIP2 which recruits the TAK1 complex (Hasegawa et al. 2008).
R-HSA-741386 (Reactome) RIP2 induces the K63-linked ubiquitination of NEMO at K285 and K399, positively modulating subsequent NF-kappaB activation (Abbot et al. 2007). TRAF6 E3 ligase is capable of performing this ubiquitination step when overexpressed in HEK239 cells, and this effect is blocked if RIP2 siRNA is co-transfected, but small interfering RNA (siRNA) experiments indicate that there are additional E3 ligases that can substitute for TRAF6 in NEMO ubiquitination. In addition to TRAF6, the K63-specific E2 ligase Ubc13 is required for NEMO ubiquitination suggesting a common mechanism for NEMO ubiquitination in NOD and TLR signaling.
R-HSA-741395 (Reactome) CARD9 binds RIP2 and NOD2. In addition overexpression of CARD9 strongly activates the kinases p38 and Jnk while CARD9-deficient mouse macrophages have defects in activation of p38 and Jnk but not NF-kappaB signaling, suggesting that CARD9 is involved in an NF-kappaB-independent signaling pathway (Hsu et al. 2007), but the mechanism is unclear. CARD9 is the key transducer of signals from dectin-1, the major mammalian pattern recognition receptor for the fungal component zymosan (Gross et al. 2006).
R-HSA-741411 (Reactome) RIP2-induced ubiquitination of NEMO and consequent NFkappaB activation can be reversed in a dose-responsive manner by the deubiquitinase CYLD, suggesting that CYLD negatively regulates RIP2-induced NEMO ubiquitinylation.
R-HSA-844438 (Reactome) NLRP1 in the presence of Mg2+ was seen to have altered electrophoretic mobility when MDP was added. This was interpreted as evidence of NLRP1 oligomerization. The extent of oligomerization is unknown.
R-HSA-844440 (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-844447 (Reactome) In vitro studies using purified NLRP1 and caspase-1 suggest that MDP induces a conformational change in NLRP1 that allows it to bind nucleotides and oligomerize, creating a binding platform for caspase-1 (Faustin et al. 2008). There is no direct evidence that NLRP1 binds MDP so the mechanism that stimulates NLRP1 is unclear.
R-HSA-844610 (Reactome) NLRP3 interacts with ASC (Manji et al. 2003) via their PYD domains (Dowds et al. 2004). NLRP3 oligomerization leads to PYD domain clustering which is believed to facilitate the interaction of NLRP3 with the PYD domain of ASC (Schroder & Tschopp, 2010).
R-HSA-844612 (Reactome) Procaspase-1 is recruited via a CARD-CARD interaction with ASC. This creates procaspase-1 clustering which is believed to stimulate procaspase-1 autocleavage, generating the p10/p20 fragments that assemble into the active capsase-1 tetramer (Schroder & Tschopp, 2010).
R-HSA-844617 (Reactome) IPAF contains an N-terminal CARD domain, a central nucleotide-binding domain, and a C-terminal regulatory leucine-rich repeat domain. IPAF associates with the CARD domain of procaspase-1 through a CARD-CARD interaction.
R-HSA-844618 (Reactome) The ASC CARD domain recruits procaspase-1 leading to autoactivation, generating caspase-1.
R-HSA-844619 (Reactome) AIM2 binds to cytosolic dsDNA via its C-terminal HIN domain. The source of the dsDNA can be can be viral, bacterial or derived from the host (Hornung et al. 2009, Muruve et al. 2008). Multiple AIM2 molecules may bind the same dsDNA (Fernandes-Alnemri et al. 2008).
R-HSA-844620 (Reactome)