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

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1029, 3223, 286, 11, 4138, 4541411613, 2912, 21, 423084, 3330483018, 19, 3520, 3627, 3930349462226714, 40, 4431, 43, 47425, 374140522NOD1iE-DAP NLRP3 elicitor small moleculesNLRP3 NOD1iE-DAP oligomer Pyrin trimer Oxidized thioredoxinTXNIP PAMPNOD oligomer MDPNOD2 oligomer NOD1iE-DAP MDPNOD2 oligomer NOD1iE-DAP oligomer MDPNOD2 MDPNOD2 oligomer MDPNOD2 oligomer MDPNOD2 NLRP3 elicitor proteins PAMPNOD oligomerK63-polyUb-RIP2NEMOactivated TAK1 complex pUb-TRAF6TAB1TAB2/TAB3free polyubiquitin chain phospho-TAK1 NOD1iE-DAP oligomer Ubc13UBE2V1 PAMPNOD oligomerK63-polyUb-RIP2NEMOactivated TAK1 complex PAMPNOD oligomerRIP2 NOD1iE-DAP oligomer NLRP3 elicitor proteinsNLRP3 NLRP3 elicitorsNLRP3 oligomerASC NLRP3 elicitor proteinsNLRP3 PAMPNOD oligomerRIP2 PAMPNOD oligomer PAMPNOD oligomerRIP2NEMO NOD1iE-DAP Activated IKK Complex NOD1iE-DAP MDPNOD2 PAMPNOD oligomerK63-Ub-RIP2 MDPNOD2 oligomer IKKAIKKBNEMO NOD1iE-DAP PAMPNOD oligomerK63-polyUb-RIP2NEMO NLRP3 elicitorsNLRP3 oligomerASC p-IRAK2K63-linked pUb oligo-TRAF6free K63-linked pUbp-TAK1complex NOD1iE-DAP oligomer hp-IRAK1K6-polyUb TRAF6 NOD1iE-DAP MDPNOD2 oligomer TAB2/3 PSTPIP1 trimerPyrin trimer MDPNLRP1 SUGT1HSP90 PAMPNOD oligomer MDPNOD2 MDPNLRP1ATP NLRP3 elicitorsNLRP3 PAMPNOD oligomerK63-polyUb-RIP2NEMO NLRP3 elicitor small molecules IPAF elicitors IPAF elicitors NOD1iE-DAP mitochondrial matrixNOD1iE-DAP oligomer MDPNOD2 TAB2/3 PAMPNOD oligomerRIP2 PAMPNOD oligomerK63-Ub-RIP2 PAMPNOD oligomerK63-Ub-RIP2 ATPP2X7 PSTPIP1 trimer MDPNOD2 ATPP2X7 oligomer TAK1 complex ATPP2X7 oligomerPannexin-1 Pyrin trimer PAMPNOD oligomer MDPNOD2 oligomer MDPNOD2 PAMPNOD oligomerRIP2 Activated TAK complexes NOD1iE-DAP oligomer Bcl-2/Bcl-XMDPNOD2 dsDNAAIM2 oligomerASC Pyrin trimer IPAF elicitorsNLRC4Procaspase-1 Pyrin trimerASC cytosoldsDNAAIM2 oligomerASC PAMPNOD oligomer TAB2/3 MDPNOD2 hp-IRAK1K6-poly-Ub oligo-TRAF6Activated TAK1 complex TAB2/3 MDPNLRP1 NLRP3SUGT1HSP90 NLRP3SUGT1HSP90 ATPP2X7 oligomer p-IRAK2K63-linked pUb oligo-TRAF6 MDPNOD2 NLRP3 elicitor proteins NOD1iE-DAP NOD1iE-DAP oligomer SUGT1HSP90 MDPNOD2 TRAF6 E3/E2 ubiquitin ligase complex NLRP3 elicitor small molecules SUGT1HSP90 NLRP3 elicitor small moleculesNLRP3 TAK1 complex PAMPNOD oligomerRIP2K63-Ub-K285-NEMO PSTPIP1 trimer dsDNAAIM2 NOD1iE-DAP NLRP3SUGT1HSP90 dsDNAAIM2 oligomerASCProcaspase-1 PAMPNOD oligomerRIP2CARD9 PAMPNOD oligomerK63-polyUb-RIP2NEMO ATPP2X7 NOD1iE-DAP oligomer NOD1iE-DAP TAK1 complex TAK1 complex hp-IRAK1K6 poly-Ub oligo-TRAF6 NOD1iE-DAP oligomer MDPNOD2 oligomer NOD1iE-DAP NOD1iE-DAPLong prodomain caspases PAMPNOD oligomerK63-Ub-RIP2 PAMPNOD oligomer PAMPNOD oligomerK63-polyUb-RIP2NEMO IPAF elicitorsNLRC4 PAMPNOD oligomer IPAF elicitorsNLRC4 MDPNOD2 oligomer Bcl-2/Bcl-XMDPNOD2 oligomer ATPP2X7 TXNIPNLRP3 PAMPNOD oligomer NLRP3 elicitorsNLRP3 oligomerASCProcaspase-1 TAB2/3 PAMPNOD oligomerRIP2K63-pUb-K285-NEMO NOD1iE-DAP PAMPNOD oligomer ThioredoxinTXNIP SUGT1HSP90 PAMPNOD oligomerK63-polyUb-RIP2NEMOTAK1 complex NOD1 ADPATPMAP3K7 ATPAlpha-hemolysin TXNIPNLRP3NLRP3ATPP2X7 oligomerPannexin-1CARD9NOD1 NLRP3 IPAF elicitorsNLRC4MDPNLRP1ATPTAB2 TRAF6 E3/E2 ubiquitin ligase complexActivated TAK complexesCASP1Alpha-hemolysin dsDNAAIM2MAP3K7 NOD2 TNFAIP3MEFV NOD1 NLRP3 elicitorsNLRP3 oligomerUb-209-RIPK2 MEFV NLRC4 NOD2Ub-209-RIPK2 Asb NOD2 APPSUGT1HSP90K+ATP Activated IKK ComplexNLRP1TXNIP p-IRAK2 iE-DAP HSP90AB1 IPAF elicitorsNLRC4Procaspase-1PANX1Ub-285-IKBKG RIPK2 SUGT1 P2RX7 PYCARD iE-DAP NLRP3 elicitor proteinsTAB3TAK1 complexMDP TAB1 NOD1 CHUK TXN BCL2 p-S207,T211-MAP2K6NLRP3 SUGT1 PYCARD RIPK2 MDPNOD2 oligomerTAB3MDP IKBKG PYCARD iE-DAP APPMDP PAMPNOD oligomerK63-polyUb-RIP2NEMOactivated TAK1 complexTAB2 MAP2K6TAB3NOD1 p38 MAPKPAMPNOD oligomerDouble-stranded DNAP2RX7 NLRP3 elicitor proteinsNLRP3P2RX7 CYLDNOD1 NLRP1 IKBKGPYCARD NLRP3 IKBKG ADPdsDNAAIM2 oligomerASCProcaspase-12xHC-TXNprgJ CASP1TXNp-T184,T187-MAP3K7 PSTPIP1 PSTPIP1 trimeriE-DAP HSP90AB1TAB2 iE-DAP iE-DAP NOD1iE-DAP oligomerNLRC4dsDNAAIM2 oligomerMDP Double-stranded DNA ROSBCL2L1 p-S177,S181-IKBKB Pyrin trimerASCRIP2 ubiquitin ligasesHSP90AB1 HUA PSTPIP1 IKBKB NLRC4 ATPP2X7UBE2V1 TAB3Oxidized thioredoxinTXNIPp-2S,S376,T,T209,T387-IRAK1 MDP MDP PAMPNOD oligomerRIP2CARD9K+MAP3K7 NOD1 NOD2 PAMPNOD oligomerRIP2NEMONOD2 iE-DAP MDPATPP2X7 oligomerNLRP3 elicitor small moleculesMDPNLRP1NOD1 TAB1 NLRP3 NLRP3 elicitor small moleculesNLRP3NOD2 CASP1TXNIP TAB3iE-DAP Phospho-p38 MAPKIKBKG Pyrin trimerATP K63polyUbiE-DAP TRAF6 TAB1 IKBKG PANX1 AIM2TXNIPATPNLRP3 elicitorsNLRP3TXNIP IKKAIKKBNEMOAsb MDP K63polyUb TRAF6 PSTPIP1 trimerPyrin trimerp-S176,S180-CHUK UBE2N SiO2 SUGT1 Ub-209-RIPK2 NOD2 MEFV MDPNOD2HSP90AB1 NLRP1 MDP SiO2 IKBKG NLRP1 SUGT1NOD1iE-DAPLong prodomain caspasesBcl-2/Bcl-XCARD9 NOD1NOD2 dsDNAAIM2 oligomerASCPAMPNOD oligomerK63-polyUb-RIP2NEMOMDPNLRP1ATP oligomerIPAF elicitorsIKBKG PAMPNOD oligomerK63-polyUb-RIP2NEMOTAK1 complexATP NOD2 iE-DAP NLRP3 CASP1TAB1 NLRP3SUGT1HSP90ThioredoxinTXNIPPAMPNOD oligomerRIP2NOD2 MDP ATP NOD1 HUA iE-DAP SUGT1 iE-DAPMAP3K7 Ub-209-RIPK2 NOD1iE-DAPNLRP3 elicitorsNLRP3 oligomerASCNOD1 PYCARD MDP RIPK2 ATPPYCARDBcl-2/Bcl-XP2RX7NOD1 IKBKG AIM2 MDP MDP MDP RIPK2 2xHC-TXN RIPK2TAB2 prgJ Long prodomain caspasesTAB2 NOD2 NOD1 PAMPNOD oligomerRIP2K63-pUb-K285-NEMOiE-DAP HSP90AB1 NLRP3 elicitorsNLRP3 oligomerASCProcaspase-1NOD2 15, 17, 24, 3415, 17, 342


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Wikipathways-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.

Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=168643

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History

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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)
APPProteinP05067 (Uniprot-TrEMBL)
ATP

P2X7 oligomer

Pannexin-1
ComplexREACT_76478 (Reactome)
ATP P2X7 oligomerComplexREACT_76503 (Reactome)
ATP P2X7ComplexREACT_76271 (Reactome)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated IKK ComplexComplexREACT_7826 (Reactome)
Activated TAK complexesComplexREACT_23279 (Reactome)
Alpha-hemolysin ProteinP09616 (Uniprot-TrEMBL)
Asb MetaboliteCHEBI:46661 (ChEBI)
BCL2 ProteinP10415 (Uniprot-TrEMBL)
BCL2L1 ProteinQ07817 (Uniprot-TrEMBL)
Bcl-2/Bcl-XComplexREACT_76081 (Reactome)
Bcl-2/Bcl-XProteinREACT_76436 (Reactome)
CARD9 ProteinQ9H257 (Uniprot-TrEMBL)
CARD9ProteinQ9H257 (Uniprot-TrEMBL)
CASP1ProteinP29466 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CYLDProteinQ9NQC7 (Uniprot-TrEMBL)
Double-stranded DNA MetaboliteCHEBI:16991 (ChEBI)
Double-stranded DNACHEBI:16991 (ChEBI)
HSP90AB1 ProteinP08238 (Uniprot-TrEMBL)
HSP90AB1ProteinP08238 (Uniprot-TrEMBL)
HUA MetaboliteCHEBI:16336 (ChEBI)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKBKGProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA

IKKB

NEMO
ComplexREACT_7693 (Reactome)
IPAF elicitors

NLRC4

Procaspase-1
ComplexREACT_76296 (Reactome)
IPAF elicitors NLRC4ComplexREACT_76033 (Reactome)
IPAF elicitorsREACT_76533 (Reactome)
K+MetaboliteCHEBI:29103 (ChEBI)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUbREACT_21645 (Reactome)
Long prodomain caspasesProteinREACT_76682 (Reactome)
MAP2K6ProteinP52564 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MDP

NLRP1

ATP oligomer
REACT_76874 (Reactome)
MDP

NLRP1

ATP
ComplexREACT_76210 (Reactome)
MDP NLRP1ComplexREACT_75983 (Reactome)
MDP NOD2 oligomerComplexREACT_23163 (Reactome)
MDP NOD2ComplexREACT_22502 (Reactome)
MDP MetaboliteCHEBI:59414 (ChEBI)
MDPMetaboliteCHEBI:59414 (ChEBI)
MEFV ProteinO15553 (Uniprot-TrEMBL)
NLRC4 ProteinQ9NPP4 (Uniprot-TrEMBL)
NLRC4ProteinQ9NPP4 (Uniprot-TrEMBL)
NLRP1 ProteinQ9C000 (Uniprot-TrEMBL)
NLRP1ProteinQ9C000 (Uniprot-TrEMBL)
NLRP3

SUGT1

HSP90
ComplexREACT_76613 (Reactome)
NLRP3 ProteinQ96P20 (Uniprot-TrEMBL)
NLRP3 elicitor proteins NLRP3ComplexREACT_76263 (Reactome)
NLRP3 elicitor proteinsProteinREACT_76223 (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 NLRP3ComplexREACT_76557 (Reactome)
NLRP3 elicitor small moleculesMetaboliteREACT_76093 (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 ASC

Procaspase-1
ComplexREACT_76472 (Reactome)
NLRP3 elicitors

NLRP3 oligomer

ASC
ComplexREACT_76555 (Reactome)
NLRP3 elicitors NLRP3 oligomerREACT_75982 (Reactome)
NLRP3 elicitors NLRP3ComplexREACT_76877 (Reactome)
NLRP3ProteinQ96P20 (Uniprot-TrEMBL)
NOD1

iE-DAP

Long prodomain caspases
ComplexREACT_76886 (Reactome)
NOD1 iE-DAP oligomerComplexREACT_23297 (Reactome)
NOD1 iE-DAPComplexREACT_22558 (Reactome)
NOD1 ProteinQ9Y239 (Uniprot-TrEMBL)
NOD1ProteinQ9Y239 (Uniprot-TrEMBL)
NOD2 ProteinQ9HC29 (Uniprot-TrEMBL)
NOD2ProteinQ9HC29 (Uniprot-TrEMBL)
Oxidized thioredoxin TXNIPComplexREACT_76193 (Reactome)
P2RX7 ProteinQ99572 (Uniprot-TrEMBL)
P2RX7ProteinQ99572 (Uniprot-TrEMBL)
PAMP

NOD oligomer K63-polyUb-RIP2 NEMO

TAK1 complex
ComplexREACT_76707 (Reactome)
PAMP

NOD oligomer K63-polyUb-RIP2 NEMO

activated TAK1 complex
ComplexREACT_23399 (Reactome)
PAMP

NOD oligomer K63-polyUb-RIP2

NEMO
ComplexREACT_22571 (Reactome)
PAMP

NOD oligomer RIP2

CARD9
ComplexREACT_76094 (Reactome)
PAMP

NOD oligomer RIP2

K63-pUb-K285-NEMO
ComplexREACT_76201 (Reactome)
PAMP

NOD oligomer RIP2

NEMO
ComplexREACT_76490 (Reactome)
PAMP

NOD oligomer

RIP2
ComplexREACT_76636 (Reactome)
PAMP NOD oligomerComplexREACT_22620 (Reactome)
PANX1 ProteinQ96RD7 (Uniprot-TrEMBL)
PANX1ProteinQ96RD7 (Uniprot-TrEMBL)
PSTPIP1 ProteinO43586 (Uniprot-TrEMBL)
PSTPIP1 trimer Pyrin trimerComplexREACT_76648 (Reactome)
PSTPIP1 trimerComplexREACT_76772 (Reactome)
PYCARD ProteinQ9ULZ3 (Uniprot-TrEMBL)
PYCARDProteinQ9ULZ3 (Uniprot-TrEMBL)
Phospho-p38 MAPKProteinREACT_76698 (Reactome)
Pyrin trimer ASCComplexREACT_76773 (Reactome)
Pyrin trimerComplexREACT_76209 (Reactome)
RIP2 ubiquitin ligasesComplexREACT_76470 (Reactome)
RIPK2 ProteinO43353 (Uniprot-TrEMBL)
RIPK2ProteinO43353 (Uniprot-TrEMBL)
ROSMetaboliteCHEBI:26523 (ChEBI)
SUGT1 HSP90ComplexREACT_76594 (Reactome)
SUGT1 ProteinQ9Y2Z0 (Uniprot-TrEMBL)
SUGT1ProteinQ9Y2Z0 (Uniprot-TrEMBL)
SiO2 MetaboliteCHEBI:30563 (ChEBI)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3ProteinQ8N5C8 (Uniprot-TrEMBL)
TAK1 complexComplexREACT_22633 (Reactome)
TNFAIP3ProteinP21580 (Uniprot-TrEMBL)
TRAF6 E3/E2 ubiquitin ligase complexComplexREACT_76422 (Reactome)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TXN ProteinP10599 (Uniprot-TrEMBL)
TXNIP NLRP3ComplexREACT_76813 (Reactome)
TXNIP ProteinQ9H3M7 (Uniprot-TrEMBL)
TXNIPProteinQ9H3M7 (Uniprot-TrEMBL)
TXNProteinP10599 (Uniprot-TrEMBL)
Thioredoxin TXNIPComplexREACT_76548 (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-1
ComplexREACT_76706 (Reactome)
dsDNA

AIM2 oligomer

ASC
ComplexREACT_76330 (Reactome)
dsDNA AIM2 oligomerREACT_76301 (Reactome)
dsDNA AIM2ComplexREACT_76737 (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-T184,T187-MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
p38 MAPKProteinREACT_75997 (Reactome)
prgJ ProteinP41785 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2xHC-TXNArrowREACT_75912 (Reactome)
ADPArrowREACT_22190 (Reactome)
ADPArrowREACT_6935 (Reactome)
ADPArrowREACT_75807 (Reactome)
AIM2REACT_75821 (Reactome)
ATP P2X7 oligomerREACT_75889 (Reactome)
ATP P2X7 oligomerREACT_75933 (Reactome)
ATPREACT_22190 (Reactome)
ATPREACT_6935 (Reactome)
ATPREACT_75791 (Reactome)
ATPREACT_75807 (Reactome)
ATPREACT_75872 (Reactome)
Activated IKK ComplexArrowREACT_6935 (Reactome)
Activated TAK complexesREACT_6935 (Reactome)
Bcl-2/Bcl-XREACT_75844 (Reactome)
CARD9REACT_75873 (Reactome)
CASP1REACT_75785 (Reactome)
CASP1REACT_75834 (Reactome)
CASP1REACT_75890 (Reactome)
CYLDREACT_75903 (Reactome)
Double-stranded DNAREACT_75821 (Reactome)
HSP90AB1REACT_75814 (Reactome)
IKBKGREACT_75893 (Reactome)
IKKA

IKKB

NEMO
REACT_6935 (Reactome)
IPAF elicitors NLRC4REACT_75785 (Reactome)
IPAF elicitorsREACT_75906 (Reactome)
K63polyUbArrowREACT_75888 (Reactome)
K63polyUbArrowREACT_75903 (Reactome)
K63polyUbREACT_75843 (Reactome)
K63polyUbREACT_75924 (Reactome)
Long prodomain caspasesREACT_75921 (Reactome)
MAP2K6REACT_22190 (Reactome)
MDP NLRP1REACT_75872 (Reactome)
MDPREACT_75756 (Reactome)
MDPREACT_75796 (Reactome)
NLRC4REACT_75906 (Reactome)
NLRP1REACT_75756 (Reactome)
NLRP1REACT_75844 (Reactome)
NLRP3

SUGT1

HSP90
REACT_75765 (Reactome)
NLRP3

SUGT1

HSP90
REACT_75877 (Reactome)
NLRP3 elicitor proteins NLRP3ArrowREACT_75877 (Reactome)
NLRP3 elicitor proteinsREACT_75877 (Reactome)
NLRP3 elicitor small molecules NLRP3ArrowREACT_75765 (Reactome)
NLRP3 elicitor small moleculesREACT_75765 (Reactome)
NLRP3 elicitors

NLRP3 oligomer

ASC
REACT_75834 (Reactome)
NLRP3 elicitors NLRP3 oligomerREACT_75848 (Reactome)
NLRP3REACT_75769 (Reactome)
NLRP3REACT_75932 (Reactome)
NOD1 iE-DAPREACT_75921 (Reactome)
NOD1REACT_75907 (Reactome)
NOD2REACT_75796 (Reactome)
P2RX7REACT_75791 (Reactome)
PAMP

NOD oligomer K63-polyUb-RIP2

NEMO
REACT_75887 (Reactome)
PAMP

NOD oligomer RIP2

NEMO
ArrowREACT_75888 (Reactome)
PAMP

NOD oligomer RIP2

NEMO
ArrowREACT_75903 (Reactome)
PAMP

NOD oligomer RIP2

NEMO
REACT_75843 (Reactome)
PAMP

NOD oligomer RIP2

NEMO
REACT_75924 (Reactome)
PAMP

NOD oligomer

RIP2
REACT_75873 (Reactome)
PAMP

NOD oligomer

RIP2
REACT_75893 (Reactome)
PAMP NOD oligomerREACT_75833 (Reactome)
PANX1REACT_75933 (Reactome)
PSTPIP1 trimerREACT_75934 (Reactome)
PYCARDREACT_75804 (Reactome)
PYCARDREACT_75848 (Reactome)
PYCARDREACT_75855 (Reactome)
Phospho-p38 MAPKArrowREACT_75807 (Reactome)
Pyrin trimerREACT_75855 (Reactome)
Pyrin trimerREACT_75934 (Reactome)
REACT_22190 (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).
REACT_6935 (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.

REACT_75756 (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.
REACT_75760 (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).
REACT_75761 (Reactome)