Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling (Homo sapiens)
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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
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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- 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 Scholia
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- Martinon F, Burns K, Tschopp J.; ''The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.''; PubMed Europe PMC Scholia
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- 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 Scholia
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- 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 Scholia
- 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 Scholia
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External references
DataNodes
| View all... |
| Name | Type | Database reference | Comment |
|---|---|---|---|
| 2xHC-TXN [cytosol] | Protein | P10599 (Uniprot-TrEMBL)  | |
| 2xHC-TXN | Protein | P10599 (Uniprot-TrEMBL) | |
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| AIM2 [cytosol] | Protein | O14862 (Uniprot-TrEMBL) | |
| AIM2 | Protein | O14862 (Uniprot-TrEMBL) | |
| APP(672-711) [cytosol] | Protein | P05067 (Uniprot-TrEMBL) | |
| ATP [cytosol] | Metabolite | CHEBI:15422 (ChEBI) | |
| ATP [extracellular region] | Metabolite | CHEBI:15422 (ChEBI) | |
| ATP:P2X7 oligomer:Pannexin-1 | Complex | REACT_76478 (Reactome) | |
| ATP:P2X7 oligomer | Complex | REACT_76503 (Reactome) | |
| ATP:P2X7 | Complex | REACT_76271 (Reactome) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| Activated IKK Complex | Complex | REACT_7826 (Reactome) | |
| Activated TAK complexes | Complex | REACT_23279 (Reactome) | |
| Alpha-hemolysin [cytosol] | Protein | P09616 (Uniprot-TrEMBL) | |
| Asb [cytosol] | Metabolite | CHEBI:46661 (ChEBI) | |
| BCL2 [mitochondrial outer membrane] | Protein | P10415 (Uniprot-TrEMBL) | |
| BCL2L1
[mitochondrial outer membrane] | Protein | Q07817 (Uniprot-TrEMBL) | |
| Bcl-2/Bcl-X(L):NLRP1 | Complex | REACT_76081 (Reactome) | |
| Bcl-2/Bcl-X(L) | Protein | REACT_76436 (Reactome) | |
| CARD9 [cytosol] | Protein | Q9H257 (Uniprot-TrEMBL) | |
| CARD9 | Protein | Q9H257 (Uniprot-TrEMBL) | |
| CASP1(1-404) [cytosol] | Protein | P29466 (Uniprot-TrEMBL) | |
| CASP1(1-404) | Protein | P29466 (Uniprot-TrEMBL) | |
| CHUK [cytosol] | Protein | O15111 (Uniprot-TrEMBL) | |
| CYLD | Protein | Q9NQC7 (Uniprot-TrEMBL) | |
| Double-stranded DNA [cytosol] | Metabolite | CHEBI:16991 (ChEBI) | |
| Double-stranded DNA | CHEBI:16991 (ChEBI) | ||
| HSP90AB1 [cytosol] | Protein | P08238 (Uniprot-TrEMBL) | |
| HSP90AB1 | Protein | P08238 (Uniprot-TrEMBL) | |
| HUA [cytosol] | Metabolite | CHEBI:16336 (ChEBI) | |
| IKBKB [cytosol] | Protein | O14920 (Uniprot-TrEMBL) | |
| IKBKG [cytosol] | Protein | Q9Y6K9 (Uniprot-TrEMBL) | |
| IKBKG | Protein | Q9Y6K9 (Uniprot-TrEMBL) | |
| IKKA:IKKB:NEMO | Complex | REACT_7693 (Reactome) | |
| IPAF elicitors:NLRC4:Procaspase-1 | Complex | REACT_76296 (Reactome) | |
| IPAF elicitors:NLRC4 | Complex | REACT_76033 (Reactome) | |
| IPAF elicitors | REACT_76533 (Reactome) | ||
| K+ | Metabolite | CHEBI:29103 (ChEBI) | |
| K63polyUb TRAF6 [cytosol] | Protein | Q9Y4K3 (Uniprot-TrEMBL) | |
| K63polyUb | REACT_21645 (Reactome) | ||
| Long prodomain caspases | Protein | REACT_76682 (Reactome) | |
| MAP2K6 | Protein | P52564 (Uniprot-TrEMBL) | |
| MAP3K7 [cytosol] | Protein | O43318 (Uniprot-TrEMBL) | |
| MDP [cytosol] | Metabolite | CHEBI:59414 (ChEBI) | |
| MDP:NLRP1:ATP oligomer | REACT_76874 (Reactome) | ||
| MDP:NLRP1:ATP | Complex | REACT_76210 (Reactome) | |
| MDP:NLRP1 | Complex | REACT_75983 (Reactome) | |
| MDP:NOD2 oligomer | Complex | REACT_23163 (Reactome) | |
| MDP:NOD2 | Complex | REACT_22502 (Reactome) | |
| MDP | Metabolite | CHEBI:59414 (ChEBI) | |
| MEFV [cytosol] | Protein | O15553 (Uniprot-TrEMBL) | |
| NLRC4 [cytosol] | Protein | Q9NPP4 (Uniprot-TrEMBL) | |
| NLRC4 | Protein | Q9NPP4 (Uniprot-TrEMBL) | |
| NLRP1 [cytosol] | Protein | Q9C000 (Uniprot-TrEMBL) | |
| NLRP1 | Protein | Q9C000 (Uniprot-TrEMBL) | |
| NLRP3
elicitors:NLRP3 oligomer:ASC:Procaspase-1 | Complex | REACT_76472 (Reactome) | |
| NLRP3
elicitors:NLRP3 oligomer:ASC | Complex | REACT_76555 (Reactome) | |
| NLRP3
elicitors:NLRP3 oligomer | REACT_75982 (Reactome) | ||
| NLRP3 elicitors:NLRP3 | Complex | REACT_76877 (Reactome) | |
| NLRP3 [cytosol] | Protein | Q96P20 (Uniprot-TrEMBL) | |
| NLRP3 elicitor proteins:NLRP3 | Complex | REACT_76263 (Reactome) | |
| NLRP3 elicitor proteins | Protein | REACT_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:NLRP3 | Complex | REACT_76557 (Reactome) | |
| NLRP3 elicitor small molecules | Metabolite | REACT_76093 (Reactome) | Several intact viruses, fungi and bacteria can induce NLRP3 activation, as can human proteins such as beta-amyloid (Schroder & Tschopp 2010). |
| NLRP3:SUGT1:HSP90 | Complex | REACT_76613 (Reactome) | |
| NLRP3 | Protein | Q96P20 (Uniprot-TrEMBL) | |
| NOD1 [cytosol] | Protein | Q9Y239 (Uniprot-TrEMBL) | |
| NOD1:iE-DAP oligomer | Complex | REACT_23297 (Reactome) | |
| NOD1:iE-DAP:Long prodomain caspases | Complex | REACT_76886 (Reactome) | |
| NOD1:iE-DAP | Complex | REACT_22558 (Reactome) | |
| NOD1 | Protein | Q9Y239 (Uniprot-TrEMBL) | |
| NOD2 [cytosol] | Protein | Q9HC29 (Uniprot-TrEMBL) | |
| NOD2 | Protein | Q9HC29 (Uniprot-TrEMBL) | |
| Oxidized thioredoxin:TXNIP | Complex | REACT_76193 (Reactome) | |
| P2RX7 [plasma membrane] | Protein | Q99572 (Uniprot-TrEMBL) | |
| P2RX7 | Protein | Q99572 (Uniprot-TrEMBL) | |
| PAMP:NOD
oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex | Complex | REACT_76707 (Reactome) | |
| PAMP:NOD
oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex | Complex | REACT_23399 (Reactome) | |
| PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO | Complex | REACT_22571 (Reactome) | |
| PAMP:NOD oligomer:RIP2:CARD9 | Complex | REACT_76094 (Reactome) | |
| PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMO | Complex | REACT_76201 (Reactome) | |
| PAMP:NOD oligomer:RIP2:NEMO | Complex | REACT_76490 (Reactome) | |
| PAMP:NOD oligomer:RIP2 | Complex | REACT_76636 (Reactome) | |
| PAMP:NOD oligomer | Complex | REACT_22620 (Reactome) | |
| PANX1 [plasma membrane] | Protein | Q96RD7 (Uniprot-TrEMBL) | |
| PANX1 | Protein | Q96RD7 (Uniprot-TrEMBL) | |
| PSTPIP1 [cytosol] | Protein | O43586 (Uniprot-TrEMBL) | |
| PSTPIP1 trimer:Pyrin trimer | Complex | REACT_76648 (Reactome) | |
| PSTPIP1 trimer | Complex | REACT_76772 (Reactome) | |
| PYCARD [cytosol] | Protein | Q9ULZ3 (Uniprot-TrEMBL) | |
| PYCARD | Protein | Q9ULZ3 (Uniprot-TrEMBL) | |
| Phospho-p38 MAPK | Protein | REACT_76698 (Reactome) | |
| Pyrin trimer:ASC | Complex | REACT_76773 (Reactome) | |
| Pyrin trimer | Complex | REACT_76209 (Reactome) | |
| RIP2 ubiquitin ligases | Complex | REACT_76470 (Reactome) | |
| RIPK2 [cytosol] | Protein | O43353 (Uniprot-TrEMBL) | |
| RIPK2 | Protein | O43353 (Uniprot-TrEMBL) | |
| ROS | Metabolite | CHEBI:26523 (ChEBI) | |
| SUGT1 [cytosol] | Protein | Q9Y2Z0 (Uniprot-TrEMBL) | |
| SUGT1:HSP90 | Complex | REACT_76594 (Reactome) | |
| SUGT1 | Protein | Q9Y2Z0 (Uniprot-TrEMBL) | |
| SiO2 [cytosol] | Metabolite | CHEBI:30563 (ChEBI) | |
| TAB1 [cytosol] | Protein | Q15750 (Uniprot-TrEMBL) | |
| TAB2 [cytosol] | Protein | Q9NYJ8 (Uniprot-TrEMBL) | |
| TAB2 [plasma membrane] | Protein | Q9NYJ8 (Uniprot-TrEMBL) | |
| TAB3(1-712) [cytosol] | Protein | Q8N5C8 (Uniprot-TrEMBL) | |
| TAB3(1-712) [plasma membrane] | Protein | Q8N5C8 (Uniprot-TrEMBL) | |
| TAK1 complex | Complex | REACT_22633 (Reactome) | |
| TNFAIP3(1-790) | Protein | P21580 (Uniprot-TrEMBL) | |
| TRAF6 E3/E2
ubiquitin ligase complex | Complex | REACT_76422 (Reactome) | |
| TRAF6 [cytosol] | Protein | Q9Y4K3 (Uniprot-TrEMBL) | |
| TXN [cytosol] | Protein | P10599 (Uniprot-TrEMBL) | |
| TXNIP [cytosol] | Protein | Q9H3M7 (Uniprot-TrEMBL) | |
| TXNIP:NLRP3 | Complex | REACT_76813 (Reactome) | |
| TXNIP | Protein | Q9H3M7 (Uniprot-TrEMBL) | |
| TXN | Protein | P10599 (Uniprot-TrEMBL) | |
| Thioredoxin:TXNIP | Complex | REACT_76548 (Reactome) | |
| UBE2N [cytosol] | Protein | P61088 (Uniprot-TrEMBL) | |
| UBE2V1 [cytosol] | Protein | Q13404 (Uniprot-TrEMBL) | |
| Ub-209-RIPK2 [cytosol] | Protein | O43353 (Uniprot-TrEMBL) | |
| Ub-285-IKBKG [cytosol] | Protein | Q9Y6K9 (Uniprot-TrEMBL) | |
| dsDNA:AIM2 oligomer:ASC:Procaspase-1 | Complex | REACT_76706 (Reactome) | |
| dsDNA:AIM2 oligomer:ASC | Complex | REACT_76330 (Reactome) | |
| dsDNA:AIM2 oligomer | REACT_76301 (Reactome) | ||
| dsDNA:AIM2 | Complex | REACT_76737 (Reactome) | |
| iE-DAP [cytosol] | Metabolite | CHEBI:59271 (ChEBI) | |
| iE-DAP | Metabolite | CHEBI:59271 (ChEBI) | |
| p-2S,S376,T,T209,T387-IRAK1 [cytosol] | Protein | P51617 (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 [cytosol] | Protein | O43187 (Uniprot-TrEMBL) | |
| p-S176,S180-CHUK [cytosol] | Protein | O15111 (Uniprot-TrEMBL) | |
| p-S177,S181-IKBKB [cytosol] | Protein | O14920 (Uniprot-TrEMBL) | |
| p-S207,T211-MAP2K6 | Protein | P52564 (Uniprot-TrEMBL) | |
| p-T184,T187-MAP3K7 [cytosol] | Protein | O43318 (Uniprot-TrEMBL) | |
| p38 MAPK | Protein | REACT_75997 (Reactome) | |
| prgJ [cytosol] | Protein | P41785 (Uniprot-TrEMBL) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 2xHC-TXN | Arrow | REACT_75816 (Reactome) | ||
| 2xHC-TXN | Arrow | REACT_75912 (Reactome) | ||
| ADP | Arrow | REACT_22190 (Reactome) | ||
| ADP | Arrow | REACT_6935 (Reactome) | ||
| ADP | Arrow | REACT_75807 (Reactome) | ||
| AIM2 | REACT_75821 (Reactome) | |||
| ATP:P2X7 oligomer:Pannexin-1 | Arrow | REACT_75933 (Reactome) | ||
| ATP:P2X7 oligomer | Arrow | REACT_75915 (Reactome) | ||
| ATP:P2X7 oligomer | REACT_75933 (Reactome) | |||
| ATP:P2X7 oligomer | mim-catalysis | REACT_75889 (Reactome) | ||
| ATP:P2X7 | Arrow | REACT_75791 (Reactome) | ||
| ATP:P2X7 | REACT_75915 (Reactome) | |||
| ATP | REACT_22190 (Reactome) | |||
| ATP | REACT_6935 (Reactome) | |||
| ATP | REACT_75791 (Reactome) | |||
| ATP | REACT_75807 (Reactome) | |||
| ATP | REACT_75872 (Reactome) | |||
| Activated IKK Complex | Arrow | REACT_6935 (Reactome) | ||
| Activated TAK complexes | mim-catalysis | REACT_6935 (Reactome) | ||
| Bcl-2/Bcl-X(L):NLRP1 | Arrow | REACT_75844 (Reactome) | ||
| Bcl-2/Bcl-X(L) | REACT_75844 (Reactome) | |||
| CARD9 | REACT_75873 (Reactome) | |||
| CASP1(1-404) | REACT_75785 (Reactome) | |||
| CASP1(1-404) | REACT_75834 (Reactome) | |||
| CASP1(1-404) | REACT_75890 (Reactome) | |||
| CYLD | mim-catalysis | REACT_75903 (Reactome) | ||
| Double-stranded DNA | REACT_75821 (Reactome) | |||
| HSP90AB1 | REACT_75814 (Reactome) | |||
| IKBKG | REACT_75893 (Reactome) | |||
| IKKA:IKKB:NEMO | REACT_6935 (Reactome) | |||
| IPAF elicitors:NLRC4:Procaspase-1 | Arrow | REACT_75785 (Reactome) | ||
| IPAF elicitors:NLRC4 | Arrow | REACT_75906 (Reactome) | ||
| IPAF elicitors:NLRC4 | REACT_75785 (Reactome) | |||
| IPAF elicitors | REACT_75906 (Reactome) | |||
| K+ | Arrow | REACT_75889 (Reactome) | ||
| K+ | REACT_75889 (Reactome) | |||
| K63polyUb | Arrow | REACT_75888 (Reactome) | ||
| K63polyUb | Arrow | REACT_75903 (Reactome) | ||
| K63polyUb | REACT_75843 (Reactome) | |||
| K63polyUb | REACT_75924 (Reactome) | |||
| Long prodomain caspases | REACT_75921 (Reactome) | |||
| MAP2K6 | REACT_22190 (Reactome) | |||
| MDP:NLRP1:ATP oligomer | Arrow | REACT_75818 (Reactome) | ||
| MDP:NLRP1:ATP | Arrow | REACT_75872 (Reactome) | ||
| MDP:NLRP1:ATP | REACT_75818 (Reactome) | |||
| MDP:NLRP1 | Arrow | REACT_75756 (Reactome) | ||
| MDP:NLRP1 | REACT_75872 (Reactome) | |||
| MDP:NOD2 oligomer | Arrow | REACT_75789 (Reactome) | ||
| MDP:NOD2 | Arrow | REACT_75796 (Reactome) | ||
| MDP:NOD2 | REACT_75789 (Reactome) | |||
| MDP | REACT_75756 (Reactome) | |||
| MDP | REACT_75796 (Reactome) | |||
| NLRC4 | REACT_75906 (Reactome) | |||
| NLRP1 | REACT_75756 (Reactome) | |||
| NLRP1 | REACT_75844 (Reactome) | |||
| NLRP3
elicitors:NLRP3 oligomer:ASC:Procaspase-1 | Arrow | REACT_75834 (Reactome) | ||
| NLRP3
elicitors:NLRP3 oligomer:ASC | Arrow | REACT_75848 (Reactome) | ||
| NLRP3
elicitors:NLRP3 oligomer:ASC | REACT_75834 (Reactome) | |||
| NLRP3
elicitors:NLRP3 oligomer | Arrow | REACT_75761 (Reactome) | ||
| NLRP3
elicitors:NLRP3 oligomer | REACT_75848 (Reactome) | |||
| NLRP3 elicitors:NLRP3 | REACT_75761 (Reactome) | |||
| NLRP3 elicitor proteins:NLRP3 | Arrow | REACT_75877 (Reactome) | ||
| NLRP3 elicitor proteins | REACT_75877 (Reactome) | |||
| NLRP3 elicitor small molecules:NLRP3 | Arrow | REACT_75765 (Reactome) | ||
| NLRP3 elicitor small molecules | REACT_75765 (Reactome) | |||
| NLRP3:SUGT1:HSP90 | Arrow | REACT_75769 (Reactome) | ||
| NLRP3:SUGT1:HSP90 | REACT_75765 (Reactome) | |||
| NLRP3:SUGT1:HSP90 | REACT_75877 (Reactome) | |||
| NLRP3 | REACT_75769 (Reactome) | |||
| NLRP3 | REACT_75932 (Reactome) | |||
| NOD1:iE-DAP oligomer | Arrow | REACT_75809 (Reactome) | ||
| NOD1:iE-DAP:Long prodomain caspases | Arrow | REACT_75921 (Reactome) | ||
| NOD1:iE-DAP | Arrow | REACT_75907 (Reactome) | ||
| NOD1:iE-DAP | REACT_75809 (Reactome) | |||
| NOD1:iE-DAP | REACT_75921 (Reactome) | |||
| NOD1 | REACT_75907 (Reactome) | |||
| NOD2 | REACT_75796 (Reactome) | |||
| Oxidized thioredoxin:TXNIP | REACT_75912 (Reactome) | |||
| P2RX7 | REACT_75791 (Reactome) | |||
| PAMP:NOD
oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex | Arrow | REACT_75887 (Reactome) | ||
| PAMP:NOD
oligomer:K63-polyUb-RIP2:NEMO:TAK1 complex | REACT_75766 (Reactome) | |||
| PAMP:NOD
oligomer:K63-polyUb-RIP2:NEMO:activated TAK1 complex | Arrow | REACT_75766 (Reactome) | ||
| PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO | Arrow | REACT_75843 (Reactome) | ||
| PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO | REACT_75887 (Reactome) | |||
| PAMP:NOD oligomer:K63-polyUb-RIP2:NEMO | REACT_75888 (Reactome) | |||
| PAMP:NOD oligomer:RIP2:CARD9 | Arrow | REACT_75873 (Reactome) | ||
| PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMO | Arrow | REACT_75924 (Reactome) | ||
| PAMP:NOD oligomer:RIP2:K63-pUb-K285-NEMO | REACT_75903 (Reactome) | |||
| PAMP:NOD oligomer:RIP2:NEMO | Arrow | REACT_75888 (Reactome) | ||
| PAMP:NOD oligomer:RIP2:NEMO | Arrow | REACT_75893 (Reactome) | ||
| PAMP:NOD oligomer:RIP2:NEMO | Arrow | REACT_75903 (Reactome) | ||
| PAMP:NOD oligomer:RIP2:NEMO | REACT_75843 (Reactome) | |||
| PAMP:NOD oligomer:RIP2:NEMO | REACT_75924 (Reactome) | |||
| PAMP:NOD oligomer:RIP2 | Arrow | REACT_75833 (Reactome) | ||
| PAMP:NOD oligomer:RIP2 | REACT_75873 (Reactome) | |||
| PAMP:NOD oligomer:RIP2 | REACT_75893 (Reactome) | |||
| PAMP:NOD oligomer | REACT_75833 (Reactome) | |||
| PANX1 | REACT_75933 (Reactome) | |||
| PSTPIP1 trimer:Pyrin trimer | Arrow | REACT_75934 (Reactome) | ||
| PSTPIP1 trimer | REACT_75934 (Reactome) | |||
| PYCARD | REACT_75804 (Reactome) | |||
| PYCARD | REACT_75848 (Reactome) | |||
| PYCARD | REACT_75855 (Reactome) | |||
| Phospho-p38 MAPK | Arrow | REACT_75807 (Reactome) | ||
| Pyrin trimer:ASC | Arrow | REACT_75855 (Reactome) | ||
| Pyrin trimer | REACT_75855 (Reactome) | |||
| Pyrin trimer | REACT_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) | 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). | |||
| REACT_75765 (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. | |||
| REACT_75766 (Reactome) | The TAK1 complex consists of the transforming growth factor-? (TGF-beta)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Sakurai H et al 2000; Shibuya H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Sakurai H et al 2000 ; Kishimoyo K et al 2000). The TAK1 complex is regulated by polyubiquitination. The TAK1 complex consists of the transforming growth factor-? (TGF- ?)-activated kinase (TAK1) and the TAK1-binding proteins TAB1, TAB2 and TAB3. TAK1 requires TAB1 for its kinase activity (Shibuya H et al 1996; Sakurai H et al 2000). TAB1 promotes autophosphorylation of the TAK1 kinase activation lobe, likely through an allosteric mechanism (Brown K et al 2005; Ono K 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 onto 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 leads to the activation of TAK1. 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). | |||
| REACT_75769 (Reactome) | SGT1 and HSP90 bind the NLRP3 (NALP3) LRR domain.
Genetic studies in plants suggest a role for SGT1-HSP90 as co-chaperones of plant resistance (R) proteins, serving to maintain them in an inactive but signaling-competent state. R-protein activation is beleived to lead to dissociation of the SGT1-HSP90 complex. SGT1 and HSP90 are highly conserved, while R proteins are structurally related to mammalian NLRs. Human SGT1 and HSP90 were found to bind NLRP3. Knockdown of human SGT1 by small interfering RNA or chemical inhibition of HSP90 abrogated NLRP3 inflammasome activity, indicating that they are involved in regulation of NLRP3 inflammasome signaling (Mayor et al. 2007). | |||
| REACT_75785 (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. | |||
| REACT_75789 (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). | |||
| REACT_75791 (Reactome) | P2X7 is a receptor for extracellular ATP that acts as a ligand gated non-selective cation channel. It is also responsible for the ATP-dependent lysis of macrophages, which it brings about by mediating the formation of membrane pores permeable to large molecules (Adinolfi et al. 2005). | |||
| REACT_75796 (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). | |||
| REACT_75804 (Reactome) | dsDNA:AIM2 clusters bind ASC via a PYD-PYD interaction. | |||
| REACT_75807 (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. | |||
| REACT_75809 (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). | |||
| REACT_75814 (Reactome) | The ubiquitin ligase–associated protein SGT1 (SUGT1) has two putative HSP90 binding domains, a tetratricopeptide repeat and a p23-like CHORD and Sgt1 (CS) domain. The CS domain of human SGT1 physically interacts with HSP90. SGT1 and related proteins are believed to recruit heat shock proteins to multiprotein assemblies (Lee et al. 2004). | |||
| REACT_75816 (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. | |||
| REACT_75818 (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. | |||
| REACT_75821 (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). | |||
| REACT_75833 (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). | |||
| REACT_75834 (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). | |||
| REACT_75843 (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). | |||
| REACT_75844 (Reactome) | The anti-apoptotic proteins Bcl-2 and Bcl-XL (but not Mcl-1, Bcl-W, Bfl-1 or Bcl-B) bind to NLRP1, preventing MDP-induced activation. | |||
| REACT_75848 (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). | |||
| REACT_75855 (Reactome) | Trimeric pyrin interacts with ASC through its Pyrin domains, leading to oligomerization of ASC. This interaction interferes with the ability of NLRP3 (Cyropyrin) to associate with ASC and thus inhibits inflammasome activation (Chae et al. 2003). | |||
| REACT_75859 (Reactome) | AIM2 oligomerizes, forming AIM2 clusters that are able to interact with ASC (Fernandes-Alnemri et al. 2009, Hornung et al. 2009). The extent of oligomerization required is unknown. | |||
| REACT_75872 (Reactome) | MDP may induce a conformational change in NLRP1 which enables ATP binding, required for NLRP1 oligomerization (Faustin et al. 2007). | |||
| REACT_75873 (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). | |||
| REACT_75877 (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. | |||
| REACT_75887 (Reactome) | K63-polyubiquitinated RIP2 is able to recruit the components of the TAK1 complex, which consists of TAK1, TAB1 and TAB2. | |||
| REACT_75888 (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). | |||
| REACT_75889 (Reactome) | Low level or transient activation of P2X7 leads to reversible opening of a membrane channel permeable to small cations such as Na+, Ca2+ and K+ (Adinolfi et al. 2005). | |||
| REACT_75890 (Reactome) | The ASC CARD domain recruits procaspase-1 leading to autoactivation, generating caspase-1. | |||
| REACT_75893 (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. | |||
| REACT_75903 (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. | |||
| REACT_75906 (Reactome) | Although a direct interaction between IPAF and an activating ligand has not been demonstrated, IPAF can be activated by cytosolic flagellin either applied experimentally or resulting from the activity of the virulence-associated type III or V secretion systems (Franchi et al. 2006, Miao et al 2007, 2008). Activation can also be flagellin-independent (Suzuki et al. 2007, Sutterwala et al. 2007), suggesting alternative mechanisms that are likely to involve recognition of components of the bacterial type III secretion system (Miao et al. 2010). The LRR domain of IPAF appears to repress activity in the absence of a ligand as removal of this domain leads to constitutive activation (Poyet et al. 2001). | |||
| REACT_75907 (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). | |||
| REACT_75912 (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). | |||
| REACT_75915 (Reactome) | At low to intermediate concentrations of extracellular ATP, P2X7 functions as a probably trimeric (Markwardt 2007) reversible ATP-gated, nondesensitizing cation channel. | |||
| REACT_75921 (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). | |||
| REACT_75924 (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. | |||
| REACT_75932 (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. | |||
| REACT_75933 (Reactome) | At higher concentrations of extracellular ATP, the P2X7 channel acts as an inducer of nonselective macropores permeable to large (up to 800 Da) inorganic and organic molecules. These 'death complex' pores rapidly leads to complete collapse of ionic gradients, changing the cytosolic environment from high K/ low Na/ low Cl to low K/ high Na/ high Cl (Steinberg et al. 1987, Steinberg & Silverstein 1987, Kahlenberg & Dubyak 2004). The long carboxyl-terminal cytoplasmic domain of P2X7 (352-595) appears to be crucial for P2X7 pore formation (Cheewatrakoolpong et al. 2005, Adinolfi et al. 2005). P2X7 membrane pores were recently shown to include pannexin-1 (Locovei et al. 2007). Pannexins have low homology with the invertebrate innexin gap junction proteins, reported to form gap junction channels and also to function as hemi-gap junction channels that are sensitive to gap junction channel blockers (Bruzzone et al. 2003, 2005). The P2X7 receptor is generally accepted to be part of a multimeric complex, not fully characterized (Kim et al. 2001). | |||
| REACT_75934 (Reactome) | Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) is a pyrin-binding protein, involved in regulation of the actin cytoskeleton (Li et al. 1998) and suggested as a regulator of inflammasome activation (Khare et al. 2010). A naturally occurring mutation of PSTPIP1 where Y344 is replaced by F blocks tyrosine phosphorylation and reduces pyrin binding. Mutations of PSTPIP1 that increase pyrin binding are associated with the inflammatory syndrome pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA). Expression of PSTPIP1 with these mutations in THP-11 cells resulted in substantially increased caspase-1 activation and IL-1beta secretion. PSTPIP1 binding to pyrin is believed to promote the unmasking of its PYD domain and enhance interactions with ASC, facilitating ASC oligomerization and caspase-1 recruitment (Yu et al. 2007). | |||
| RIP2 ubiquitin ligases | mim-catalysis | REACT_75843 (Reactome) | ||
| RIPK2 | REACT_75833 (Reactome) | |||
| ROS | REACT_75816 (Reactome) | |||
| SUGT1:HSP90 | Arrow | REACT_75765 (Reactome) | ||
| SUGT1:HSP90 | Arrow | REACT_75814 (Reactome) | ||
| SUGT1:HSP90 | Arrow | REACT_75877 (Reactome) | ||
| SUGT1:HSP90 | REACT_75769 (Reactome) | |||
| SUGT1 | REACT_75814 (Reactome) | |||
| TAK1 complex | REACT_75887 (Reactome) | |||
| TAK1 complex | mim-catalysis | REACT_22190 (Reactome) | ||
| TNFAIP3(1-790) | mim-catalysis | REACT_75888 (Reactome) | ||
| TRAF6 E3/E2
ubiquitin ligase complex | mim-catalysis | REACT_75924 (Reactome) | ||
| TXNIP:NLRP3 | Arrow | REACT_75932 (Reactome) | ||
| TXNIP | Arrow | REACT_75912 (Reactome) | ||
| TXNIP | REACT_75760 (Reactome) | |||
| TXNIP | REACT_75932 (Reactome) | |||
| TXN | REACT_75760 (Reactome) | |||
| TXN | REACT_75816 (Reactome) | |||
| Thioredoxin:TXNIP | Arrow | REACT_75760 (Reactome) | ||
| dsDNA:AIM2 oligomer:ASC:Procaspase-1 | Arrow | REACT_75890 (Reactome) | ||
| dsDNA:AIM2 oligomer:ASC | Arrow | REACT_75804 (Reactome) | ||
| dsDNA:AIM2 oligomer:ASC | REACT_75890 (Reactome) | |||
| dsDNA:AIM2 oligomer | Arrow | REACT_75859 (Reactome) | ||
| dsDNA:AIM2 oligomer | REACT_75804 (Reactome) | |||
| dsDNA:AIM2 | Arrow | REACT_75821 (Reactome) | ||
| dsDNA:AIM2 | REACT_75859 (Reactome) | |||
| iE-DAP | REACT_75907 (Reactome) | |||
| p-S207,T211-MAP2K6 | Arrow | REACT_22190 (Reactome) | ||
| p-S207,T211-MAP2K6 | mim-catalysis | REACT_75807 (Reactome) | ||
| p38 MAPK | REACT_75807 (Reactome) |
