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

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4017, 4110, 32, 3415, 22, 391, 18, 354545463744, 47161043311, 27, 333774, 13129, 29, 3845142, 374, 19320, 25294537830, 31295213624, 26MDPNOD2 oligomer NLRP3 elicitor small molecules NOD1iE-DAP Bcl-2/Bcl-XThioredoxinTXNIP NOD1iE-DAP oligomer MDPNOD2 MDPNOD2 oligomer MDPNOD2 NOD1iE-DAP PAMPNOD oligomerK63-polyUb-RIP2NEMO MDPNOD2 MDPNOD2 pUb-TRAF6TAB1TAB2/TAB3free polyubiquitin chain phospho-TAK1 NLRP3SUGT1HSP90 PAMPNOD oligomerK63-polyUb-RIP2NEMO TAB2/3 NOD1iE-DAP TXNIPNLRP3 PAMPNOD oligomerK63-polyUb-RIP2NEMO PAMPNOD oligomer NOD1iE-DAP NLRP3 elicitor proteins NLRP3 elicitorsNLRP3 oligomerASCProcaspase-1 NLRP3 elicitor proteins PAMPNOD oligomer NOD1iE-DAP oligomer PAMPNOD oligomerRIP2 MDPNOD2 Activated TAK complexes MDPNOD2 oligomer PAMPNOD oligomerRIP2K63-pUb-K285-NEMO PAMPNOD oligomer MDPNOD2 Activated IKK Complex MDPNOD2 oligomer PAMPNOD oligomerK63-Ub-RIP2 Pyrin trimer p-IRAK2K63-linked pUb oligo-TRAF6 NOD1iE-DAP TAK1 complex MDPNOD2 oligomer MDPNOD2 NOD1iE-DAPLong prodomain caspases PSTPIP1 trimer MDPNLRP1ATP NLRP3 elicitor small moleculesNLRP3 NOD1iE-DAP oligomer PAMPNOD oligomerRIP2 MDPNLRP1 NLRP3 elicitor proteinsNLRP3 PAMPNOD oligomerK63-Ub-RIP2 IKKAIKKBNEMO NLRP3 elicitor proteinsNLRP3 IPAF elicitorsNLRC4Procaspase-1 MDPNOD2 oligomer NOD1iE-DAP TAK1 complex PAMPNOD oligomerK63-polyUb-RIP2NEMOactivated TAK1 complex PAMPNOD oligomer PAMPNOD oligomer PAMPNOD oligomer ATPP2X7 oligomerPannexin-1 Pyrin trimer PAMPNOD oligomer ATPP2X7 TAB2/3 ATPP2X7 oligomer Pyrin trimerASC NOD1iE-DAP oligomer MDPNOD2 ATPP2X7 PAMPNOD oligomer hp-IRAK1K6-poly-Ub oligo-TRAF6Activated TAK1 complex NOD1iE-DAP MDPNLRP1 NOD1iE-DAP oligomer dsDNAAIM2 oligomerASCProcaspase-1 PSTPIP1 trimer IPAF elicitorsNLRC4 Pyrin trimer mitochondrial matrixdsDNAAIM2 NOD1iE-DAP oligomer PAMPNOD oligomerK63-polyUb-RIP2NEMOTAK1 complex PAMPNOD oligomerRIP2NEMO hp-IRAK1K6 poly-Ub oligo-TRAF6 p-IRAK2K63-linked pUb oligo-TRAF6free K63-linked pUbp-TAK1complex dsDNAAIM2 oligomerASC NOD1iE-DAP SUGT1HSP90 SUGT1HSP90 ATPP2X7 cytosolTAK1 complex NLRP3SUGT1HSP90 MDPNOD2 oligomer NOD1iE-DAP SUGT1HSP90 TAK1 complex Ubc13UBE2V1 NLRP3 elicitorsNLRP3 oligomerASC NLRP3 elicitorsNLRP3 NLRP3 elicitor small molecules TAB2/3 PAMPNOD oligomerRIP2 PSTPIP1 trimerPyrin trimer TRAF6 E3/E2 ubiquitin ligase complex MDPNOD2 oligomer SUGT1HSP90 dsDNAAIM2 oligomerASC PAMPNOD oligomerRIP2 PAMPNOD oligomerK63-Ub-RIP2 NLRP3SUGT1HSP90 NOD1iE-DAP MDPNOD2 oligomer TAB2/3 TAB2/3 hp-IRAK1K6-polyUb TRAF6 NOD1iE-DAP MDPNOD2 PAMPNOD oligomerRIP2CARD9 NOD1iE-DAP PAMPNOD oligomer NOD1iE-DAP oligomer PAMPNOD oligomerK63-Ub-RIP2 IPAF elicitors NOD1iE-DAP oligomer IPAF elicitors MDPNOD2 Bcl-2/Bcl-XMDPNOD2 ATPP2X7 oligomer Oxidized thioredoxinTXNIP NOD1iE-DAP oligomer NLRP3 elicitorsNLRP3 oligomerASC PAMPNOD oligomerK63-polyUb-RIP2NEMOactivated TAK1 complex PAMPNOD oligomerRIP2K63-Ub-K285-NEMO MDPNOD2 oligomer NOD1iE-DAP oligomer IPAF elicitorsNLRC4 NLRP3 elicitor small moleculesNLRP3 PAMPNOD oligomerK63-polyUb-RIP2NEMO iE-DAP NLRP3 elicitorsNLRP3 oligomerP2RX7TAB1 MDPNLRP1ATPAPPNLRP3 PYCARDP2RX7 PAMPNOD oligomerRIP2CARD9iE-DAP HSP90AB1 NLRC4 MDP TAB3TRAF6 p-2S,S376,T,T209,T387-IRAK1 Pyrin trimerAPPDouble-stranded DNA TAB1 MDP TAK1 complexPYCARD iE-DAP MDPNLRP1ATP oligomerNOD1 Pyrin trimerASCprgJ MDPNOD1 NLRP3 MDP NLRP3 HSP90AB1 K+K+IKBKG Bcl-2/Bcl-XROSNOD2SUGT1 CASP1ATPP2X7 oligomerPannexin-1CYLDNOD1 NLRP3 elicitor small moleculesNLRP3ATP dsDNAAIM2 oligomerASCProcaspase-1NOD2 NLRP3 elicitor proteinsNLRP3PAMPNOD oligomerK63-polyUb-RIP2NEMOTAK1 complexMAP3K7 p-T184,T187-MAP3K7 TAB2 iE-DAP IKBKB TXNIP BCL2L1 ATPTXNIP HUA PSTPIP1 trimerNOD1 NOD2 IKBKG NLRP1 Ub-209-RIPK2 CASP1NOD2 NLRP3 RIPK2IKBKG TAB3ADPNOD1iE-DAPLong prodomain caspasesiE-DAP Phospho-p38 MAPKNOD1 TRAF6 E3/E2 ubiquitin ligase complexATP Alpha-hemolysin ATP PAMPNOD oligomerK63-polyUb-RIP2NEMOiE-DAP MDPNLRP1PAMPNOD oligomerRIP2NEMOCASP1HSP90AB1 ATPActivated TAK complexesPYCARD TXNp-S207,T211-MAP2K6NLRP3 elicitorsNLRP3 oligomerASCProcaspase-1ThioredoxinTXNIPTAB2 MEFV PSTPIP1 NOD2 NLRP3TAB3CARD9NOD2 NOD1 IPAF elicitorsNLRC4NLRP3 elicitor proteinsIKBKGAIM2 Long prodomain caspasesNLRP1 ADPMEFV TXNIPSUGT1 SiO2 PSTPIP1 trimerPyrin trimerIKBKG prgJ P2RX7 iE-DAPRIP2 ubiquitin ligasesPAMPNOD oligomerK63-polyUb-RIP2NEMOactivated TAK1 complex2xHC-TXN K63polyUb TRAF6 MAP3K7 IKBKG CARD9 PANX1TAB1 iE-DAP MDP RIPK2 MDP NOD2 MDPNOD2P2RX7 SUGT1HSP90MDP iE-DAP TAB2 SUGT1HUA MDP NLRC4 Oxidized thioredoxinTXNIPp-IRAK2 NOD2 MAP2K6p-S176,S180-CHUK MEFV ATPP2X7 oligomerPAMPNOD oligomerRIP2K63-pUb-K285-NEMONOD2 UBE2N TAB2 K63polyUbNLRP3SUGT1HSP90Double-stranded DNATXNIPNLRP3Activated IKK ComplexAlpha-hemolysin 2xHC-TXNCHUK IKKAIKKBNEMOPAMPNOD oligomerRIP2MAP3K7 PSTPIP1 p-S177,S181-IKBKB UBE2V1 Asb NLRP3 elicitor small moleculesNOD1 MDP Bcl-2/Bcl-XNOD2 SUGT1 ATP NLRP1 Asb Ub-209-RIPK2 NOD1ATPHSP90AB1NOD1 NLRP1RIPK2 NOD1iE-DAPMDP PYCARD IKBKG dsDNAAIM2 oligomerNLRC4Ub-209-RIPK2 IKBKG PANX1 MDP NOD2 HSP90AB1 dsDNAAIM2TAB2 NLRP3 TXN RIPK2 MDP NOD1iE-DAP oligomerdsDNAAIM2 oligomerASCiE-DAP SiO2 NOD2 NLRP3 elicitorsNLRP3TAB1 NOD1 NOD1 PYCARD iE-DAP CASP1Ub-285-IKBKG NOD1 p38 MAPKNLRP3 elicitorsNLRP3 oligomerASCBCL2 ATPP2X7iE-DAP Ub-209-RIPK2 AIM2TNFAIP3ATPMAP3K7 NOD1 TXNIP PAMPNOD oligomerTAB3IPAF elicitorsNLRC4Procaspase-1IPAF elicitorsTAB3MDP iE-DAP RIPK2 MDPNOD2 oligomerSUGT1 PYCARD MDP 4223, 28, 486, 23, 28, 48


No 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.

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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
  2. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed
  3. Schroder K, Tschopp J.; ''The inflammasomes.''; PubMed
  4. Martinon F, Burns K, Tschopp J.; ''The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.''; PubMed
  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
  6. Cockcroft S, Gomperts BD.; ''ATP induces nucleotide permeability in rat mast cells.''; PubMed
  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
  8. Kishimoto K, Matsumoto K, Ninomiya-Tsuji J.; ''TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop.''; PubMed
  9. Tatham PE, Lindau M.; ''ATP-induced pore formation in the plasma membrane of rat peritoneal mast cells.''; PubMed
  10. Markwardt F, Löhn M, Böhm T, Klapperstück M.; ''Purinoceptor-operated cationic channels in human B lymphocytes.''; PubMed
  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
  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
  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
  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
  15. Pelegrin P, Surprenant A.; ''Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor.''; PubMed
  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
  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
  18. Martinon F, Gaide O, Pétrilli V, Mayor A, Tschopp J.; ''NALP inflammasomes: a central role in innate immunity.''; PubMed
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  36. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed
  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
  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
  39. Chen G, Shaw MH, Kim YG, Nuñez G.; ''NOD-like receptors: role in innate immunity and inflammatory disease.''; PubMed
  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
  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
  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
  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
  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
  45. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J.; ''Thioredoxin-interacting protein links oxidative stress to inflammasome activation.''; PubMed
  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
  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
  48. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed
  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
  50. Cheung PC, Nebreda AR, Cohen P.; ''TAB3, a new binding partner of the protein kinase TAK1.''; PubMed
  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
  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
  53. Jo EK, Kim JK, Shin DM, Sasakawa C.; ''Molecular mechanisms regulating NLRP3 inflammasome activation.''; PubMed
  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


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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


View all...
NameTypeDatabase referenceComment
2xHC-TXN ProteinP10599 (Uniprot-TrEMBL)
2xHC-TXNProteinP10599 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AIM2 ProteinO14862 (Uniprot-TrEMBL)
AIM2ProteinO14862 (Uniprot-TrEMBL)
APPProteinP05067 (Uniprot-TrEMBL)

P2X7 oligomer

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 DNAMetaboliteCHEBI:16991 (ChEBI)
HSP90AB1 ProteinP08238 (Uniprot-TrEMBL)
HSP90AB1ProteinP08238 (Uniprot-TrEMBL)
HUA MetaboliteCHEBI:16336 (ChEBI)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKBKGProteinQ9Y6K9 (Uniprot-TrEMBL)


ComplexREACT_7693 (Reactome)
IPAF elicitors


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)


ATP oligomer
REACT_76874 (Reactome)


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)


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

ComplexREACT_76472 (Reactome)
NLRP3 elicitors

NLRP3 oligomer

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


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)

NOD oligomer K63-polyUb-RIP2 NEMO

TAK1 complex
ComplexREACT_76707 (Reactome)

NOD oligomer K63-polyUb-RIP2 NEMO

activated TAK1 complex
ComplexREACT_23399 (Reactome)

NOD oligomer K63-polyUb-RIP2

ComplexREACT_22571 (Reactome)

NOD oligomer RIP2

ComplexREACT_76094 (Reactome)

NOD oligomer RIP2

ComplexREACT_76201 (Reactome)

NOD oligomer RIP2

ComplexREACT_76490 (Reactome)

NOD oligomer

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)

AIM2 oligomer ASC

ComplexREACT_76706 (Reactome)

AIM2 oligomer

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_75933 (Reactome)
ATP P2X7 oligomermim-catalysisREACT_75889 (Reactome)
ATPREACT_22190 (Reactome)
ATPREACT_6935 (Reactome)
ATPREACT_75791 (Reactome)
ATPREACT_75807 (Reactome)
ATPREACT_75872 (Reactome)
Activated IKK ComplexArrowREACT_6935 (Reactome)
Activated TAK complexesmim-catalysisREACT_6935 (Reactome)
Bcl-2/Bcl-XREACT_75844 (Reactome)
CARD9REACT_75873 (Reactome)
CASP1REACT_75785 (Reactome)
CASP1REACT_75834 (Reactome)
CASP1REACT_75890 (Reactome)
CYLDmim-catalysisREACT_75903 (Reactome)
Double-stranded DNAREACT_75821 (Reactome)
HSP90AB1REACT_75814 (Reactome)
IKBKGREACT_75893 (Reactome)


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)


REACT_75765 (Reactome)


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

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)

NOD oligomer K63-polyUb-RIP2

REACT_75887 (Reactome)

NOD oligomer RIP2

ArrowREACT_75888 (Reactome)

NOD oligomer RIP2

ArrowREACT_75903 (Reactome)

NOD oligomer RIP2

REACT_75843 (Reactome)

NOD oligomer RIP2

REACT_75924 (Reactome)

NOD oligomer

REACT_75873 (Reactome)

NOD oligomer

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)