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  3. PubMed:23702978

PubMed: 23702978

Title
Activation and regulation of the inflammasomes.
Journal
Nature reviews. Immunology
Volume
13
Issue
None
Pages
397-411
Date
2013-06-01
Authors
Xiao TS | Latz E | Stutz A

Evidence 814fda10b5
JSON

RIG-I is widely known as a PRR that senses RNA and that signals via mitochondrial antiviral signalling protein (MAVS) to induce an interferon (IFN) response2, and IFI16 has been suggested to be a DNA sensor that signals via the protein STING (stimulator of IFN genes; also known as TMEM173) to generate an IFN response23.

a(CHEBI:"DNA polyanion") increases act(p(HGNC:IFI16)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph

a(CHEBI:"RNA fragment") increases act(p(HGNC:DDX58)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph

act(p(HGNC:DDX58)) increases act(p(HGNC:MAVS)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph

act(p(HGNC:IFI16)) increases act(p(HGNC:TMEM173)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph

act(p(HGNC:MAVS)) increases bp(GO:"response to type I interferon") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph

act(p(HGNC:TMEM173)) increases bp(GO:"response to type I interferon") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph

Evidence 40a81d6a00
JSON

One checkpoint is that bacterial mRNA from live bacteria (also known as vita-PAMPs)44 activates NLRP3; the other checkpoint is that TLR4- and TRIF (TIR domain-containing adaptor protein inducing IFNβ)-dependent signalling — which is triggered by bacterial lipopolysaccharide (LPS) — mediate the secretion of type I IFNs, inducing pro-caspase 11 expression and activation by triggering the IFNα/β receptor (IFNAR) (FIG. 1).

a(CHEBI:"LPS with O-antigen") increases bp(GO:"TRIF-dependent toll-like receptor 4 signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interferon signaling subgraph

bp(GO:"TRIF-dependent toll-like receptor 4 signaling pathway") regulates sec(a(MESH:"Interferon Type I")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interferon signaling subgraph

bp(GO:"TRIF-dependent toll-like receptor 4 signaling pathway") increases p(HGNC:SCAF11) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interferon signaling subgraph

bp(GO:"TRIF-dependent toll-like receptor 4 signaling pathway") increases act(p(HGNC:IFNAR1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interferon signaling subgraph

act(p(HGNC:IFNAR1)) increases act(p(HGNC:SCAF11)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interferon signaling subgraph

Evidence 8fead530a9
JSON

A few molecules, such as amyloid-β, can induce both NLRP3 priming through TLR activation and NLRP3 inflammasome activation68.

a(CHEBI:"amyloid-beta") increases act(p(HGNC:NLRP3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"amyloid-beta") increases act(p(FPLX:TLR)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"amyloid-beta") increases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence d8cdbc5378
JSON

The mobilized Ca2+ has many molecular targets, including TGFβ-activated kinase 1 (TAK1; also known as MAP3K7) (REF. 86).

p(HGNC:MAP3K7) association a(CHEBI:"calcium(2+)") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space

a(CHEBI:"calcium(2+)") association p(HGNC:MAP3K7) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space

Evidence 0348d300d1
JSON

This channel senses intracellular ROS and responds by opening itself to facilitate Ca2+ influx into the cell; this is intriguing considering that both ion fluxes and the oxidative state (see below) have important roles in NLRP3 inflammasome activation.

tloc(a(CHEBI:"calcium(2+)"), fromLoc(MESH:"Extracellular Space"), toLoc(MESH:"Intracellular Space")) increases act(p(HGNC:NLRP3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"reactive oxygen species") increases act(p(HGNC:TRPM2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

act(p(HGNC:TRPM2)) increases tloc(a(CHEBI:"calcium(2+)"), fromLoc(MESH:"Extracellular Space"), toLoc(MESH:"Intracellular Space")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence f22416eda7
JSON

NLRP1 recognizes muramyl dipeptide, which is a bacterial peptidoglycan

a(CHEBI:"muramyl dipeptide") increases act(p(HGNC:NLRP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low

Evidence 6054b77776
JSON

In addition, T cell-derived IFNγ has been shown to downregulate the activity of NLRP3 via activation of inducible nitric oxide synthase (iNOS) in a mouse model of tuberculosis71; nitric oxide (NO) induces NLRP3 nitrosylation and thereby inhibits NLRP3 activity.

a(CHEBI:"nitric oxide") increases p(HGNC:NLRP3, pmod(NO)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Nitric oxide subgraph

p(HGNC:IFNG) decreases act(p(HGNC:NLRP3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Nitric oxide subgraph

p(HGNC:IFNG) increases act(p(HGNC:NOS2)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Nitric oxide subgraph

p(HGNC:NLRP3, pmod(NO)) decreases act(p(HGNC:NLRP3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Nitric oxide subgraph

act(p(HGNC:NOS2)) increases a(CHEBI:"nitric oxide") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Nitric oxide subgraph

Evidence d43ef1780a
JSON

Indeed, the binding of cytochrome c that has been released from mitochondria to apoptotic protease-activating factor 1 (APAF1) and the subsequent assembly of the apoptosome only occurs when subphysiological K+ concentrations are reached in compromised cells77,78.

a(CHEBI:"potassium(1+)") decreases bp(GO:"apoptosome assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
XIAP subgraph

complex(p(HGNC:APAF1), p(HGNC:CYCS)) increases bp(GO:"apoptosome assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
XIAP subgraph

tloc(p(HGNC:CYCS), fromLoc(MESH:Mitochondria), toLoc(MESH:Cytosol)) increases complex(p(HGNC:APAF1), p(HGNC:CYCS)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
XIAP subgraph

Evidence 1aa1ef910a
JSON

Similarly, activation of the NLRP1B and NLRP3 inflammasomes depends on low K+ concentrations in intracellular compartments79, and a low K+ concentration promotes the assembly of the ASC speck6.

a(CHEBI:"potassium(1+)") increases act(complex(GO:"NLRP1 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"potassium(1+)") increases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space
NeuroMMSigDB
Caspase subgraph

a(CHEBI:"potassium(1+)") increases act(p(HGNC:PYCARD)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Intracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence 63774838a4
JSON

In addition, high extracellular levels of K+ can block IL-1β release after NLRC4 and AIM2 inflammasome formation80,81, which indicates that low intracellular K+ levels might also be required for the activation of these inflammasomes.

a(CHEBI:"potassium(1+)") decreases sec(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence bd2ec5cf0f
JSON

In particular, ROS facilitate the assembly of the apoptosome in several ways.

a(CHEBI:"reactive oxygen species") increases bp(GO:"apoptosome assembly") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Apoptosis signaling subgraph

Evidence 4f3863b75c
JSON

In the presence of the translation inhibitor cycloheximide, TRIF signalling that is downstream of TLR3 or TLR4 leads to pro-IL-1β processing by caspase 8 (REF. 55).

a(CHEBI:cycloheximide) increases bp(GO:"TRIF-dependent toll-like receptor 4 signaling pathway") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

bp(GO:"TRIF-dependent toll-like receptor 4 signaling pathway") increases act(p(HGNC:CASP8)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:CASP8)) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 6374fbe840
JSON

In addition, type I IFNs can reduce IL-1β and IL-18 release by functioning at two levels.

a(MESH:"Interferon Type I") decreases sec(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Interleukin signaling subgraph

a(MESH:"Interferon Type I") decreases sec(p(HGNC:IL18)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 3438fbff3c
JSON

IFNs upregulate AIM2 expression but they downregulate IL-1β expression and inhibit the NLRP3 inflammasome.

a(MESH:Interferons) increases p(HGNC:AIM2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Interleukin signaling subgraph

a(MESH:Interferons) decreases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Interleukin signaling subgraph

a(MESH:Interferons) decreases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence d45cb486cd
JSON

Thus, it is not surprising that effector and memory CD4+ T cells have the capacity to inhibit the activation of the NLRP1 and NLRP3 inflammasomes in a contact-dependent manner, possibly via TNFR superfamily molecules such as CD40 ligand (CD40L)70.

bp(GO:"CD4-positive, alpha-beta T cell activation") decreases act(complex(GO:"NLRP1 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

bp(GO:"CD4-positive, alpha-beta T cell activation") decreases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence 8ad24d2dfd
JSON

The transcription of pro-IL-1β is induced by the activation of the transcription factor nuclear factor-κB (NF-κB), whereas pro-IL-18 is constitutively expressed and its expression is increased after cellular activation.

bp(GO:"cell activation") increases p(HGNC:IL18) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Nuclear factor Kappa beta subgraph

p(HGNC:NFKB1) increases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Nuclear factor Kappa beta subgraph

Evidence fe22bf6c86
JSON

Furthermore, in response to genotoxic stress, the ripoptosome assembles and activates caspase 8.

bp(GO:"cellular response to DNA damage stimulus") increases complex(GO:ripoptosome) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

complex(GO:ripoptosome) increases act(p(HGNC:CASP8)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence 491eae70a6
JSON

The authors proposed that another, not yet characterized, ER stress pathway activates the NLRP3 inflammasome90.

bp(GO:"response to endoplasmic reticulum stress") increases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence 4d5c5e2b3b
JSON

Furthermore, autophagy can regulate both apoptosis and inflammasome assembly, and, depending on the conditions, can be either pro- or anti-apoptotic104

bp(GO:autophagy) regulates bp(GO:"apoptotic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Apoptosis signaling subgraph

bp(GO:autophagy) regulates complex(GO:"inflammasome complex") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Apoptosis signaling subgraph

Evidence 04b2fe20d7
JSON

For inflammasome activation and IL-1β release, autophagy is a negative regulator:

bp(GO:autophagy) decreases act(complex(GO:"inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Interleukin signaling subgraph

bp(GO:autophagy) decreases sec(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 0edd18a10e
JSON

NLRC4 and NLRP1 can both activate caspase 1 through their CARDs without recruiting ASC; however, the recruitment of ASC greatly enhances the formation of the complex and the processing of IL-1β7,13–16.

complex(GO:"IPAF inflammasome complex") increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

complex(GO:"NLRP1 inflammasome complex") increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

composite(complex(GO:"NLRP1 inflammasome complex"), p(HGNC:PYCARD)) increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

composite(complex(GO:"IPAF inflammasome complex"), p(HGNC:PYCARD)) increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence 86f7924c79
JSON

In the original description of the inflammasome, human NLRP1 was shown to recruit and to activate an additional inflammatory caspase, namely caspase 5, via its CARD3.

complex(GO:"NLRP1 inflammasome complex") increases act(p(HGNC:CASP5)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence dbf3f2e47f
JSON

Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18.

complex(GO:"inflammasome complex") increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph

complex(GO:"inflammasome complex") increases act(p(HGNC:IL18)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 6d6508a0f2
JSON

Once the protein complexes have formed, the inflammasomes activate caspase 1, which proteolytically activates the pro-inflammatory cytokines interleukin-1β (IL-1β)3 and IL-18.

complex(GO:"inflammasome complex") increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:CASP1)) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:CASP1)) increases act(p(HGNC:IL18)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 1b9bfce108
JSON

Indeed, inflammasomes (which induce pyroptosis through caspase 1 or caspase 11 activation) and apoptosomes (which activate caspase 9 in response to cytochrome c release from mitochondria) are two mechanisms by which compromised cells are eliminated.

complex(GO:"inflammasome complex") increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
XIAP subgraph

complex(GO:"inflammasome complex") increases bp(GO:pyroptosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
XIAP subgraph

complex(GO:"inflammasome complex") increases act(p(HGNC:SCAF11)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
XIAP subgraph

act(complex(GO:apoptosome)) increases act(p(HGNC:CASP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
XIAP subgraph

tloc(p(HGNC:CYCS), fromLoc(MESH:Mitochondria), toLoc(MESH:Cytosol)) increases act(complex(GO:apoptosome)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
XIAP subgraph

act(p(HGNC:CASP1)) increases bp(GO:pyroptosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
XIAP subgraph

act(p(HGNC:SCAF11)) increases bp(GO:pyroptosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
XIAP subgraph

Evidence eab9a89287
JSON

In addition, inflammasome activation causes a rapid, proinflammatory form of cell death called pyroptosis4.

act(complex(GO:"inflammasome complex")) increases bp(GO:pyroptosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Apoptosis signaling subgraph

Evidence b580da5b84
JSON

The formation of this complex activates RIP3, which is necessary for the cleavage of pro-IL-1β by both the NLRP3-caspase 1 and the caspase 8 pathways56 (FIG. 1).

complex(GO:ripoptosome) increases act(p(HGNC:RIPK3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:RIPK3)) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:RIPK3)) increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:RIPK3)) increases act(p(HGNC:CASP8)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 7b2bdc8e67
JSON

NLRP1 has been shown to bind directly to its ligand muramyl dipeptide in vitro and this was demonstrated to be sufficient to activate the assembly of an inflammasome.

complex(a(CHEBI:"muramyl dipeptide"), p(HGNC:NLRP1)) increases act(complex(GO:"inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 49ad3e47e3
JSON

Using its CARD, ASC brings monomers of procaspase 1 into close proximity, which initiates caspase 1 self- cleavage and the formation of the active heterotetrameric caspase 1.

p(HGNC:PYCARD) increases complex(p(HGNC:CASP1), p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

complex(p(HGNC:CASP1), p(HGNC:CASP1)) increases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence bd519f3603
JSON

CARD8 has multiple functions in regulating apoptosis, one of which is to directly bind to procaspase 9 and to suppress its activation109.

complex(p(HGNC:CARD8), p(HGNC:CASP9)) decreases act(p(HGNC:CASP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence ee8c6a36d0
JSON

Active caspase 1 proteolytically activates a number of proteins8, including pro-IL-1β and pro-IL-18 (REFS 9,10), and induces their release via a non-classical secretion pathway11.

act(p(HGNC:CASP1)) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:CASP1)) increases sec(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:CASP1)) increases act(p(HGNC:IL18)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:CASP1)) increases sec(p(HGNC:IL18)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence d67555c42e
JSON

Caspase 1mediated activation of members of the IL-1β cytokine family leads to the recruitment and the activation of other immune cells, such as neutrophils, at the site of infection and/or tissue damage.

act(p(HGNC:CASP1)) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:IL1B)) increases bp(GO:"neutrophil activation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 2ceaafd380
JSON

Similarly, mouse caspase 12, which is a paralogue of caspase 1, interacts with caspase 1 to reduce its activity110

complex(p(HGNC:CASP1), p(MGI:Casp12)) decreases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence b64272fc00
JSON

For example, following sensing of fungal components by the PRR dectin 1 that is expressed on human dendritic cells, signalling via the kinase SYK leads to the formation of a complex that is composed of caspase 8 and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1); this complex binds to ASC, which possibly recruits cleavage substrates53. The MALT1-ASC-caspase 8 complex directly mediates IL-1β maturation53.

complex(p(HGNC:CASP8), p(HGNC:MALT1)) increases complex(p(HGNC:CASP8), p(HGNC:MALT1), p(HGNC:PYCARD)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

complex(p(HGNC:CASP8), p(HGNC:MALT1), p(HGNC:PYCARD)) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:CLEC7A)) increases act(p(HGNC:SYK)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

act(p(HGNC:SYK)) increases complex(p(HGNC:CASP8), p(HGNC:MALT1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 22f30dddb4
JSON

One additional factor that can mediate IL-1β processing and activation is caspase 8 (FIG. 1)

p(HGNC:CASP8) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence 6253133985
JSON

In addition, it was recently shown that CD95 signalling mediates IL-1β and IL-18 processing through the activation of caspase 8 (REF. 60) (FIG. 1).

act(p(HGNC:CASP8)) regulates act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Tumor necrosis factor subgraph

act(p(HGNC:CASP8)) regulates act(p(HGNC:IL18)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Tumor necrosis factor subgraph

act(p(HGNC:FAS)) increases act(p(HGNC:CASP8)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Tumor necrosis factor subgraph

Evidence 9c15c5c47b
JSON

Pyroptosis in response to live Gram-negative bacteria but not in response to other inflammasome triggers is entirely dependent on caspase 11, whereas caspase 1 is dispensable for this process41

p(HGNC:SCAF11) increases bp(GO:pyroptosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Apoptosis signaling subgraph

Evidence 091df25602
JSON

However, a requirement for the interaction of NLRP1 with nucleotide-binding oligomerization domain-containing protein 2 (NOD2), which is another receptor for muramyl dipeptide, has been described.

complex(p(HGNC:NLRP1), p(HGNC:NOD2)) increases act(complex(GO:"inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium

Evidence 6682d5cee8
JSON

Finally, heat shock proteins (HSPs) also have important roles in the regulation of cell death, and it has been shown that HSP90 and the cochaperone ubiquitin ligase-associated protein SGT1 are required for NLRP3 activation (REF. 129).

composite(p(FPLX:HSP90), p(HGNC:SUGT1)) increases act(p(HGNC:NLRP3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence d0b3c79560
JSON

It is known that about 60% of patients with cryopyrin-associated periodic syndrome (CAPS) carry activating mutations in the coding sequence of NLRP3 itself or in other inflammasome components69.

g(HGNC:NLRP3, var("?")) positiveCorrelation path(MESH:"Cryopyrin-Associated Periodic Syndromes") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

path(MESH:"Cryopyrin-Associated Periodic Syndromes") positiveCorrelation g(HGNC:NLRP3, var("?")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence fc8aefdfcb
JSON

Furthermore, the amount of NLRP3 mRNA is tightly regulated by the microRNA miR-223, which leads to decreased NLRP3 protein levels and, thus, influences the threshold of NLRP3 activation74,75.

m(HGNC:MIR223) decreases p(HGNC:NLRP3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Caspase subgraph

Evidence d29340b167
JSON

In addition, AIM2 expression can be induced by IFNβ and IFNγ65,66.

p(FPLX:IFNB) increases p(HGNC:AIM2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph

p(HGNC:IFNG) increases p(HGNC:AIM2) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 32b51ab8ac
JSON

First, a bacterial Toll-like receptor (TLR) activator leads to cellular priming and upregulation of NLRP3 and pro-IL-1β expression (the priming checkpoint in the standard model)37,38.

act(p(FPLX:TLR)) increases p(HGNC:NLRP3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph

act(p(FPLX:TLR)) increases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 184c74e2a9
JSON

Many innate immune signalling or cytokine receptors, such as the TNFR, activate transcription of NLRP3 and thereby influence the susceptibility of immune cells to NLRP3 inflammasome triggers37,38 (FIG. 2).

p(FPLX:TNFRSF) increases p(HGNC:NLRP3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Tumor necrosis factor subgraph

Evidence c759585c21
JSON

The ripoptosome contains caspase 8, FAS-associated death domain protein (FADD) and receptor-interacting protein 1 (RIP1; also known as RIPK1), and forms spontaneously in response to loss or inhibition of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP), inhibitor of apoptosis protein 1 (IAP1; also known as BIRC3) and IAP2 (also known as BIRC2) (REF 56).

p(HGNC:BIRC2) decreases complex(GO:ripoptosome) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Toll like receptor subgraph

p(HGNC:BIRC3) decreases complex(GO:ripoptosome) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Toll like receptor subgraph

p(HGNC:XIAP) decreases complex(GO:ripoptosome) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Toll like receptor subgraph

Evidence 515978f7f1
JSON

NLRP3 deubiquitylation is mediated by the K63-specific deubiquitinase BRCC3 (REF. 63).

p(HGNC:BRCC3) decreases p(HGNC:NLRP3, pmod(Ub)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Caspase subgraph

Evidence 4e78399aca
JSON

CARD-only proteins (COPs) can also inhibit caspase 1 activation112. CARD18 (also known as ICEBERG) and CARD16 (also known as pseudoICE and COP1) were the first ‘decoy’ COPs to be described113.

p(HGNC:CARD16) decreases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

p(HGNC:CARD18) decreases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence 5d9ee75b22
JSON

CARD17 (also known as INCA), which is another decoy protein, is upregulated by IFNγ to suppress IL-1β generation114.

p(HGNC:CARD17) decreases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Interleukin signaling subgraph

p(HGNC:IFNG) increases p(HGNC:CARD17) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 8168e54883
JSON

By contrast, nitrosylation of caspase 9 inhibits its function94. Similarly, caspase 1 can be inhibited by nitrosylation95, which suggests that modification by reactive molecules is a general mechanism for the regulation of caspase activity.

p(HGNC:CASP1, pmod(NO)) decreases act(p(HGNC:CASP1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

p(HGNC:CASP9, pmod(NO)) decreases act(p(HGNC:CASP9)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence 0a0e27a22a
JSON

Another regulator of Ca2+, namely C/EPB-homologous protein (CHOP; also known as DDIT3), has been implicated in NLRP3 inflammasome activation89

p(HGNC:DDIT3) regulates a(CHEBI:"calcium(2+)") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

p(HGNC:DDIT3) increases act(complex(GO:"NLRP3 inflammasome complex")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence 5982584a7b
JSON

Protein synthesis could be inhibited by the phosphorylation of the initiation factor eukaryotic translation initiation factor 2 subunit-α (EIF2α; also known as EIF2S1).

p(HGNC:EIF2S1, pmod(Ph)) decreases bp(GO:translation) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space

Evidence 425f5998ef
JSON

Indeed, activation of the TNFR family member CD95 (also known as FAS) can induce IL-1β processing that is independent of inflammasomes and of caspase 1 (REF. 59).

act(p(HGNC:FAS)) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph
NeuroMMSigDB
Tumor necrosis factor subgraph

Evidence c35346fd67
JSON

Even if the expression of pro-caspase 11 could be induced independently of IFN signalling, caspase 11 activation in macrophages in response to Salmonella enterica subsp. enterica serovar Typhimurium infection is dependent on IFNAR1 as well as signal tranducer and activator of transcription 1 (STAT1)46.

p(HGNC:IFNAR1) increases act(p(HGNC:SCAF11)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph

act(p(HGNC:STAT1)) increases act(p(HGNC:SCAF11)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Caspase subgraph
NeuroMMSigDB
Interferon signaling subgraph

Evidence 0693b6d86a
JSON

In addition, IL-1α, which also activates IL-1R, could contribute to the inflammatory response in vivo.

p(HGNC:IL1A) increases act(p(HGNC:IL1R1)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interleukin signaling subgraph

p(HGNC:IL1A) increases bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Interleukin signaling subgraph

Evidence bf676049ff
JSON

In mice, NAIP (NLR family, apoptosis inhibitory protein) family proteins sense the proteinaceous NLRC4 activators and, in turn, activate the assembly of the NLRC4 inflammasome.

act(p(HGNC:NAIP)) increases complex(GO:"IPAF inflammasome complex") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 74d7382a19
JSON

In the context of NLRC4 activation, caspase 11 was shown to interact with cofilin.

act(p(HGNC:NLRC4)) increases complex(p(HGNC:CFL1), p(HGNC:SCAF11)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
NeuroMMSigDB
Apoptosis signaling subgraph
NeuroMMSigDB
Regulation of actin cytoskeleton subgraph

Evidence b73dbd5f92
JSON

Indeed, NLRP12 can function as a positive regulator of dendritic cell migration or as a negative regulator of non-canonical NFκB signalling20,21, and NLRP6 can negatively regulate innate immunity22.

p(HGNC:NLRP6) increases bp(GO:"negative regulation of innate immune response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:NLRP12) increases bp(GO:"dendritic cell migration") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

p(HGNC:NLRP12) increases bp(GO:"negative regulation of NIK/NF-kappaB signaling") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence a6a0a8739a
JSON

NLRC4 can only be activated by S . Typhimurium after a specific serine residue has been phosphorylated by protein kinase Cδ (PKCδ; encoded by PRKCD ), which depends on the recognition of both flagellin and the type III secretion system.

act(p(HGNC:PRKCD), ma(kin)) increases p(HGNC:NLRC4, pmod(Ph, Ser)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interferon signaling subgraph

Evidence 666d726b0d
JSON

Indeed, a number of non-caspase proteases such as proteinase 3 have the ability to activate IL-1β in an inflammasome-independent manner11.

p(HGNC:PRTN3) increases act(p(HGNC:IL1B)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
NeuroMMSigDB
Interleukin signaling subgraph

Evidence 9a1d383acf
JSON

POP1 (also known as PYDC1 and ASC2) and POP2 (also known as PYDC2) inhibit the interactions between the inflammasome sensor molecules and ASC115–117.

p(HGNC:PYDC1) decreases complex(complex(GO:"inflammasome complex"), p(HGNC:PYCARD)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

p(HGNC:PYDC2) decreases complex(complex(GO:"inflammasome complex"), p(HGNC:PYCARD)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence 225de51513
JSON

Another transient receptor potential channel — TRPM2 — has also been implicated in NLRP3 activation in response to crystalline substances88.

p(HGNC:TRPM2) increases act(p(HGNC:NLRP3)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Extracellular Space
NeuroMMSigDB
Caspase subgraph

Evidence eea0c390a1
JSON

One study found that Mefv deletion in mice lead to increased IL-1β release without influencing caspase 1 activity or inflammasome assembly.

p(MGI:Mefv) decreases sec(p(MGI:Il1b)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space
NeuroMMSigDB
Interleukin signaling subgraph

Evidence e42b4e52f5
JSON

At the same time, we have learnt that immune dysregulation contributes to prevalent diseases in Western societies such as atherosclerosis, type 2 diabetes, cancer and neurodegenerative diseases.

path(MESH:"Immune System Diseases") increases path(MESH:Atherosclerosis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Immune System Diseases") increases path(MESH:"Diabetes Mellitus, Type 2") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

path(MESH:"Immune System Diseases") increases path(MESH:"Neurodegenerative Diseases") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.