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


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.


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

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  1. Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A, Chiu YH, Deng L, Chen ZJ.; ''TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains.''; PubMed Europe PMC
  2. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC
  3. Schroder K, Tschopp J.; ''The inflammasomes.''; PubMed Europe PMC
  4. Martinon F, Burns K, Tschopp J.; ''The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.''; PubMed Europe PMC
  5. Enslen H, Raingeaud J, Davis RJ.; ''Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6.''; PubMed Europe PMC
  6. Cockcroft S, Gomperts BD.; ''ATP induces nucleotide permeability in rat mast cells.''; PubMed Europe PMC
  7. Craven RR, Gao X, Allen IC, Gris D, Bubeck Wardenburg J, McElvania-Tekippe E, Ting JP, Duncan JA.; ''Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells.''; PubMed Europe PMC
  8. Kishimoto K, Matsumoto K, Ninomiya-Tsuji J.; ''TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.''; PubMed Europe PMC
  9. Tatham PE, Lindau M.; ''ATP-induced pore formation in the plasma membrane of rat peritoneal mast cells.''; PubMed Europe PMC
  10. Markwardt F, Löhn M, Böhm T, Klapperstück M.; ''Purinoceptor-operated cationic channels in human B lymphocytes.''; PubMed Europe PMC
  11. Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G.; ''An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome.''; PubMed Europe PMC
  12. Liyanage NP, Fernando MR, Lou MF.; ''Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2).''; PubMed Europe PMC
  13. Poyet JL, Srinivasula SM, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri ES.; ''Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1.''; PubMed Europe PMC
  14. Ishitani T, Takaesu G, Ninomiya-Tsuji J, Shibuya H, Gaynor RB, Matsumoto K.; ''Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling.''; PubMed Europe PMC
  15. Pelegrin P, Surprenant A.; ''Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.''; PubMed Europe PMC
  16. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMed Europe PMC
  17. Abbott DW, Yang Y, Hutti JE, Madhavarapu S, Kelliher MA, Cantley LC.; ''Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains.''; PubMed Europe PMC
  18. Martinon F, Gaide O, Pétrilli V, Mayor A, Tschopp J.; ''NALP inflammasomes: a central role in innate immunity.''; PubMed Europe PMC
  19. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nuñez G.; ''Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease.''; PubMed Europe PMC
  20. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT.; ''The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.''; PubMed Europe PMC
  21. Richards N, Schaner P, Diaz A, Stuckey J, Shelden E, Wadhwa A, Gumucio DL.; ''Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis.''; PubMed Europe PMC
  22. Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, Kastner DL.; ''Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway.''; PubMed Europe PMC
  23. Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Núñez G, Inohara N.; ''A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation.''; PubMed Europe PMC
  24. Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E.; ''Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.''; PubMed Europe PMC
  25. Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, Ogura Y, Kawasaki A, Fukase K, Kusumoto S, Valvano MA, Foster SJ, Mak TW, Nuñez G, Inohara N.; ''An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid.''; PubMed Europe PMC
  26. Zhao L, Kwon MJ, Huang S, Lee JY, Fukase K, Inohara N, Hwang DH.; ''Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116 cells.''; PubMed Europe PMC
  27. Lee YT, Jacob J, Michowski W, Nowotny M, Kuznicki J, Chazin WJ.; ''Human Sgt1 binds HSP90 through the CHORD-Sgt1 domain and not the tetratricopeptide repeat domain.''; PubMed Europe PMC
  28. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA, Sutterwala FS.; ''The Nalp3 inflammasome is essential for the development of silicosis.''; PubMed Europe PMC
  29. Yamasaki K, Muto J, Taylor KR, Cogen AL, Audish D, Bertin J, Grant EP, Coyle AJ, Misaghi A, Hoffman HM, Gallo RL.; ''NLRP3/cryopyrin is necessary for interleukin-1beta (IL-1beta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury.''; PubMed Europe PMC
  30. Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES.; ''The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.''; PubMed Europe PMC
  31. Di Virgilio F, Chiozzi P, Ferrari D, Falzoni S, Sanz JM, Morelli A, Torboli M, Bolognesi G, Baricordi OR.; ''Nucleotide receptors: an emerging family of regulatory molecules in blood cells.''; PubMed Europe PMC
  32. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G.; ''Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB.''; PubMed Europe PMC
  33. Kovalenko A, Chable-Bessia C, Cantarella G, Israël A, Wallach D, Courtois G.; ''The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination.''; PubMed Europe PMC
  34. Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, Matsuzawa S, Terskikh AV, Faustin B, Reed JC.; ''Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1.''; PubMed Europe PMC
  35. Inohara N, Koseki T, del Peso L, Hu Y, Yee C, Chen S, Carrio R, Merino J, Liu D, Ni J, Núñez G.; ''Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB.''; PubMed Europe PMC
  36. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed Europe PMC
  37. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jéhanno M, Viala J, Tedin K, Taha MK, Labigne A, Zähringer U, Coyle AJ, DiStefano PS, Bertin J, Sansonetti PJ, Philpott DJ.; ''Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan.''; PubMed Europe PMC
  38. Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed Europe PMC
  39. Chen G, Shaw MH, Kim YG, Nuñez G.; ''NOD-like receptors: role in innate immunity and inflammatory disease.''; PubMed Europe PMC
  40. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA.; ''AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC.''; PubMed Europe PMC
  41. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC
  42. Abbott DW, Wilkins A, Asara JM, Cantley LC.; ''The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO.''; PubMed Europe PMC
  43. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES.; ''AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA.''; PubMed Europe PMC
  44. Bertin J, Nir WJ, Fischer CM, Tayber OV, Errada PR, Grant JR, Keilty JJ, Gosselin ML, Robison KE, Wong GH, Glucksmann MA, DiStefano PS.; ''Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB.''; PubMed Europe PMC
  45. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J.; ''Thioredoxin-interacting protein links oxidative stress to inflammasome activation.''; PubMed Europe PMC
  46. Arch RH, Gedrich RW, Thompson CB.; ''Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death.''; PubMed Europe PMC
  47. Mayor A, Martinon F, De Smedt T, Pétrilli V, Tschopp J.; ''A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses.''; PubMed Europe PMC
  48. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC
  49. Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, Philpott DJ, Sansonetti PJ.; ''Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection.''; PubMed Europe PMC
  50. Cheung PC, Nebreda AR, Cohen P.; ''TAB3, a new binding partner of the protein kinase TAK1.''; PubMed Europe PMC
  51. Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Núñez G.; ''Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product.''; PubMed Europe PMC
  52. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC.; ''Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation.''; PubMed Europe PMC
  53. Jo EK, Kim JK, Shin DM, Sasakawa C.; ''Molecular mechanisms regulating NLRP3 inflammasome activation.''; PubMed Europe PMC
  54. Manji GA, Wang L, Geddes BJ, Brown M, Merriam S, Al-Garawi A, Mak S, Lora JM, Briskin M, Jurman M, Cao J, DiStefano PS, Bertin J.; ''PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B.''; PubMed Europe PMC


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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


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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)


ComplexR-HSA-925458 (Reactome)


ComplexR-HSA-877381 (Reactome)


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)

ubiquitin ligase

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)


ArrowR-HSA-844612 (Reactome)


ArrowR-HSA-844610 (Reactome)


R-HSA-844612 (Reactome)


ArrowR-HSA-1296421 (Reactome)


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 a