Original Literature | Model OverView |
---|---|
Publication
Title
The Troll in Toll: Mal and Tram as bridges for TLR2 and TLR4 signaling.
Affiliation
School of Biochemistry and Immunology, Trinity College, Dublin, Ireland.sheedyf@tcd.ie
Abstract
Signaling by two of the most important bacteria-sensing TLRs, TLR2 and TLR4,involves two adaptor proteins, MyD88 adaptor-like (Mal) and Toll/IL-1 receptor(TIR) domain-containing adaptor-inducing IFN-beta (Trif)-related adaptormolecule (TRAM). Recently, new insights into the functioning of these twoadapters have emerged. Mal is required by both TLRs to act as a bridge torecruit the adaptor MyD88, leading ultimately to NF-kappaB activation.Similarly, TRAM acts as a bridge to recruit TRIF to the TLR4 complex, leading toactivation of the transcription factor IFN regulatory factor 3. Consistent withMal and TRAM being key points of control, recent evidence suggests that they aresubject to regulation by phosphorylation. Further, a variant in Mal in humanshas been found to protect against multiple infectious diseases. Finally, anotherTIR domain-containing adaptor, sterile alpha and HEAT/armadillo motif protein(SARM), has been shown to act as an inhibitor of TRIF-dependent signaling. Theserecent discoveries add to the complexity of TLR signaling and highlight specificcontrol mechanisms for TLR2 and TLR4 signaling.
PMID
17449723
|
Entity
TRAF6
--
MO000000212
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m183
10
infinite
0
InterPro | IPR001841 |
TRANSPATH | MO000000212 |
--
IRAK-1
--
MO000000213
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m184
10
infinite
0
InterPro | IPR000719 |
TRANSPATH | MO000000213 |
--
TNF-alpha
--
MO000000289
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m230
10
infinite
0
InterPro | IPR003636 |
TRANSPATH | MO000000289 |
--
MyD88
--
MO000016573
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m1572
10
infinite
0
InterPro | IPR000157 |
TRANSPATH | MO000016573 |
--
PKCepsilon
--
MO000016645
cso30:c:Protein
cso30:i:CC_CellComponent
--
--
csml-variable:Double
m1629
10
infinite
0
InterPro | IPR000719 |
TRANSPATH | MO000016645 |
--
LPS
--
MO000016882
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m155666
10
infinite
0
TRANSPATH | MO000016882 |
--
integrins
--
MO000017291
cso30:c:Protein
cso30:i:CC_CellComponent
--
--
csml-variable:Double
m2142
10
infinite
0
TRANSPATH | MO000017291 |
--
TLR4 : TLR4
--
MO000019394
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m3961
10
infinite
0
InterPro | IPR000157 |
TRANSPATH | MO000019394 |
--
proIL-1beta
--
MO000019449
cso30:c:Protein
cso30:i:CC_CellComponent
--
--
csml-variable:Double
m4012
10
infinite
0
InterPro | IPR003297 |
TRANSPATH | MO000019449 |
--
protein remnants
--
MO000019479
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m360980
10
infinite
0
TRANSPATH | MO000019479 |
--
p50:RelA-p65{p}
--
MO000033294
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m11984
10
infinite
0
TRANSPATH | MO000033294 |
--
TRIF
--
MO000041125
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m18998
10
infinite
0
TRANSPATH | MO000041125 |
--
IRF-3{p}
--
MO000041456
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m19324
10
infinite
0
TRANSPATH | MO000041456 |
--
MAL
--
MO000068831
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m43675
10
infinite
0
TRANSPATH | MO000068831 |
--
--
e1
cso30:c:EntityBiologicalCompartment
cso30:i:CC_PlasmaMembrane
--
--
--
csml-variable:Double
m1
0
infinite
0
--
--
e10
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Cytosol
--
--
--
csml-variable:Double
m10
0
infinite
0
--
LPS: TLR4: TLR4
--
e11
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m11
0
infinite
0
--
LPS: TLR4: TLR4: MAL
--
e13
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m13
0
infinite
0
--
TLR adaptor
--
e15
cso30:c:Protein
cso30:i:CC_Cytosol
--
--
csml-variable:Double
m15
0
infinite
0
--
TLR ligand: TLR: TLR adaptor
--
e16
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m16
0
infinite
0
--
TLR ligand: TLR: TLR adaptor: IRAK-1
--
e17
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m18
0
infinite
0
--
TLR ligand: TLR: TLR adaptor: IRAK: TRAF6
--
e18
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m19
0
infinite
0
--
IRFs
--
e19
cso30:c:Protein
cso30:i:CC_Cytosol
--
--
csml-variable:Double
m22
0
infinite
0
--
--
e2
cso30:c:EntityBiologicalCompartment
cso30:i:CC_PlasmaMembrane_ExternalSideOfPlasmaMembrane_
--
--
--
csml-variable:Double
m2
0
infinite
0
--
IRFs {activated}
--
e20
cso30:c:Protein
cso30:i:CC_Cytosol
--
csml-variable:Double
m23
0
infinite
0
--
p50:RelA-p65
--
e21
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m17
10
infinite
0
TRANSPATH | MO000016632 |
--
csml-variable:Double
m24
0
infinite
0
--
MAL: PIP2
--
e23
cso30:c:Complex
cso30:i:CC_Cytosol
--
csml-variable:Double
m25
0
infinite
0
--
LPS: TLR4: TLR4: MAL: MyD88
--
e24
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m26
0
infinite
0
--
LPS: TLR4: TLR4: MAL: MyD88: IRAK-1: IRAK-4
--
e25
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m27
0
infinite
0
--
MAL: TRAF6
--
e26
cso30:c:Complex
cso30:i:CC_Cytosol
--
--
csml-variable:Double
m28
0
infinite
0
--
LPS: TLR4: TLR4: MAL: MyD88: IRAK-1: IRAK-4: TRAF6
--
e27
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m29
0
infinite
0
--
Btk {activated}
--
e28
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m30
10
infinite
0
InterPro | IPR001452 |
TRANSPATH | MO000001935 |
--
TLR2 ligand
--
e29
cso30:c:Protein
cso30:i:CC_Extracellular
--
--
csml-variable:Double
m31
0
infinite
0
--
--
e3
cso30:c:EntityBiologicalCompartment
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
--
--
csml-variable:Double
m3
0
infinite
0
--
TLR2 ligand: TLR2
--
e30
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m32
0
infinite
0
--
LPS: TLR4: TLR4: MAL {p}: MyD88: IRAK-1: IRAK-4: TRAF6
--
e31
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m33
0
infinite
0
--
LPS: TLR4: TLR4: MAL {p}: MyD88: IRAK-1: IRAK-4: TRAF6: SOCS-1
--
e32
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m34
0
infinite
0
--
LPS: TLR4: MAL {p}{ub}: MyD88: IRAK-1: IRAK-4: TRAF6: SOCS-1
--
e33
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m35
0
infinite
0
--
E3 ligase
--
e34
cso30:c:Protein
cso30:i:CC_Cytosol
--
--
csml-variable:Double
m36
0
infinite
0
--
TLR2 ligand: TLR2: MAL
--
e35
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m37
0
infinite
0
--
TLR2 ligand: TLR2: MAL: MyD88
--
e36
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m38
0
infinite
0
--
LPS: TLR4: TLR4: TRAM {myristoylated}
--
e37
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m39
0
infinite
0
--
LPS: TLR4: TLR4: TRAM{myristpylated}: TRIF
--
e38
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m40
0
infinite
0
--
IRF-1 [activated}
--
e39
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m41
10
infinite
0
InterPro | IPR001346 |
TRANSPATH | MO000007685 |
--
--
e4
cso30:c:EntityBiologicalCompartment
cso30:i:CC_PlasmaMembrane_InternalSideOfPlasmaMembrane_
--
--
--
csml-variable:Double
m4
0
infinite
0
--
IRF-5 {activated}
--
e41
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m43
10
infinite
0
InterPro | IPR008984 |
TRANSPATH | MO000007700 |
--
IRF-7 {activated}
--
e42
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m44
10
infinite
0
TRANSPATH | MO000007702 |
--
LPS: TLR4: TLR4: TRAM{myristpylated}: TRIF: TBK1
--
e44
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m46
0
infinite
0
--
TRAM {myristpylated}
--
e45
cso30:c:Protein
cso30:i:CC_Cytosol
--
csml-variable:Double
m47
0
infinite
0
--
LPS: TLR4: TLR4: TRAM{myristpylated}: TRIF: TRAF6: RIP1
--
e46
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m49
0
infinite
0
--
PKCepsilon {activated}
--
e47
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m63
10
infinite
0
InterPro | IPR000719 |
TRANSPATH | MO000016645 |
--
LPS: TLR4: TLR4: TRAM{myristpylated} {p}: TRIF: TBK1
--
e48
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m64
0
infinite
0
--
LPS: TLR4: TLR4: TRAM{myristpylated} {p}: TRIF: TRAF6: RIP1
--
e49
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m65
0
infinite
0
--
TLR ligand
--
e5
cso30:c:Protein
cso30:i:CC_Extracellular
--
--
csml-variable:Double
m5
0
infinite
0
--
--
e50
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearEnvelopeLumen
--
--
--
csml-variable:Double
m50
0
infinite
0
--
--
e51
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearPore
--
--
--
csml-variable:Double
m51
0
infinite
0
--
--
e52
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearInnerMembrane
--
--
--
csml-variable:Double
m52
0
infinite
0
--
--
e53
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearLumen
--
--
--
csml-variable:Double
m53
0
infinite
0
--
--
e54
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearOuterMembrane
--
--
--
csml-variable:Double
m54
0
infinite
0
--
--
e55
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Nucleus
--
--
--
csml-variable:Double
m55
0
infinite
0
--
--
e56
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Nucleoplasm
--
--
--
csml-variable:Double
m56
0
infinite
0
--
--
e57
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearBody
--
--
--
csml-variable:Double
m57
0
infinite
0
--
--
e58
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Nucleolus
--
--
--
csml-variable:Double
m58
0
infinite
0
--
--
e59
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearEnvelope
--
--
--
csml-variable:Double
m59
0
infinite
0
--
TLR ligand: TLR
--
e6
cso30:c:Complex
cso30:i:CC_PlasmaMembrane_IntegralToPlasmaMembrane_
--
csml-variable:Double
m6
0
infinite
0
--
--
e60
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Chromatin
--
--
--
csml-variable:Double
m60
0
infinite
0
--
--
e61
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearChromosome
--
--
--
csml-variable:Double
m61
0
infinite
0
--
--
e62
cso30:c:EntityBiologicalCompartment
cso30:i:CC_NuclearCentromere
--
--
--
csml-variable:Double
m62
0
infinite
0
--
diacyglycerol
--
e63
cso30:c:SmallMolecule
cso30:i:CC_Cytosol
--
--
csml-variable:Double
m66
0
infinite
0
--
ARF6 {activated}
--
e64
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m67
10
infinite
0
InterPro | IPR006688 |
TRANSPATH | MO000000179 |
--
PI-5K
--
e65
cso30:c:Protein
cso30:i:CC_Cytosol
--
--
csml-variable:Double
m68
0
infinite
0
--
PI-5K {activated}
--
e66
cso30:c:Protein
cso30:i:CC_Cytosol
--
csml-variable:Double
m70
0
infinite
0
--
csml-variable:Double
m71
0
infinite
0
--
SopB
--
e69
cso30:c:Protein
cso30:i:CC_Extracellular
--
--
csml-variable:Double
m73
0
infinite
0
--
--
e7
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Cell
--
--
--
csml-variable:Double
m7
0
infinite
0
--
Nalp1: Nalp3: Ipaf
--
e70
cso30:c:Complex
cso30:i:CC_Cytosol
--
--
csml-variable:Double
m74
0
infinite
0
--
PAMP
--
e71
cso30:c:SmallMolecule
cso30:i:CC_Extracellular
--
--
csml-variable:Double
m75
0
infinite
0
--
PAMP: Nalp1: Nalp3: Ipaf
--
e72
cso30:c:Complex
cso30:i:CC_Cytosol
--
csml-variable:Double
m76
0
infinite
0
--
Caspase-1 {activated}
--
e73
cso30:c:Protein
cso30:i:CC_CellComponent
--
csml-variable:Double
m77
10
infinite
0
TRANSPATH | MO000016828 |
--
Caspase-1 {activated}: MAL
--
e74
cso30:c:Complex
cso30:i:CC_Cytosol
--
csml-variable:Double
m78
0
infinite
0
--
SARM
--
e75
cso30:c:Protein
cso30:i:CC_Cytosol
--
csml-variable:Double
m79
0
infinite
0
--
TRIF: SARM
--
e76
cso30:c:Complex
cso30:i:CC_Cytosol
--
csml-variable:Double
m80
0
infinite
0
--
SARM
--
e77
cso30:c:mRNA
cso30:i:CC_Nucleoplasm
--
--
csml-variable:Double
m81
0
infinite
0
--
--
e8
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Cell_WithoutCellWall_
--
--
--
csml-variable:Double
m8
0
infinite
0
--
--
e9
cso30:c:EntityBiologicalCompartment
cso30:i:CC_Cytoplasm
--
--
--
csml-variable:Double
m9
0
infinite
0
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c1 : 1
stoichiometry:c2 : 1
stoichiometry:c3 : 1
m5*m3962*0.1
nodelay
--
0
PMID: 17449723 Upon activation, TLRs interact intracellularly with these adaptor proteins via TIR domains, and the adaptor proteins then recruit and activate downstream molecules such as IL-1R-associated kinases (IRAKs) and TNF-receptor-associated factor-6 (TRAF6), which then amplify the signal.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c27 : 1
stoichiometry:c30 : 1
m11984*0.1
nodelay
--
0
PMID: 17449723, 16698941 TLR signaling ultimately results in the activation of transcription factors such as NF-{kappa}B and IFN regulatory factors (IRFs), which promote the transcription of proinflammatory cytokines and other proteins that promote host defense.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c28 : 1
stoichiometry:c29 : 1
m23*0.1
nodelay
--
0
PMID: 17449723, 16698941 TLR signaling ultimately results in the activation of transcription factors such as NF-{kappa}B and IFN regulatory factors (IRFs), which promote the transcription of proinflammatory cytokines and other proteins that promote host defense.
p12
p12
cso30:i:ME_Colocalization
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c31 : 1
stoichiometry:c33 : 1
stoichiometry:c167 : 1
stoichiometry:c32 : 1
stoichiometry:c34 : 1
m11*m25*0.1
nodelay
--
0
PMID: 17449723 It colocalizes with TLR4. PMID: 17449723, 10589680 It was also shown that the localization of Mal to the plasma membrane by PIP2 binding is dependent on the ¦Â2-integrin CD11b in macrophages and also on the GTPase ADP ribosylation factor 6 (ARF6), which regulates production of PIP2 via activation of the enzyme PI-5K. PMID: 17449723, 16751103 his protein has been shown to interrupt Mal localization and therefore, disrupt TLR4 signaling.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c35 : 1
stoichiometry:c165 : 1
stoichiometry:c36 : 1
m1572*m13*0.1
nodelay
--
0
PMID: 17449723 This leads to MyD88 recruitment to the Mal/TLR4 complex. MyD88 can then interact with downstream signaling molecules such as IRAK-4 and IRAK-1.
p14
p14
cso30:i:ME_Binding
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c37 : 1
stoichiometry:c38 : 1
stoichiometry:c39 : 1
stoichiometry:c40 : 1
m184*m17258*m26*0.1
nodelay
--
0
PMID: 17449723 This leads to MyD88 recruitment to the Mal/TLR4 complex. MyD88 can then interact with downstream signaling molecules such as IRAK-4 and IRAK-1.
p15
p15
cso30:i:ME_Binding
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c41 : 1
stoichiometry:c42 : 1
stoichiometry:c43 : 1
m183*m43675*0.1
nodelay
--
0
PMID: 17449723 It was shown that Mal can bind TRAF6 directly and that mutating this TRAF6-binding site creates a dominant-negative mutant of NF-{kappa}B activation and activation of MAPKs by TLR2 and TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c44 : 1
stoichiometry:c46 : 1
stoichiometry:c45 : 1
m183*m27*0.1
nodelay
--
0
PMID: 17449723 MyD88 does, however, bind IRAK-1, which contains a TRAF6-binding site, leading to NF-{kappa}B activation.
p17
p17
cso30:i:ME_Phosphorylation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c47 : 1
stoichiometry:c49 : 1
stoichiometry:c48 : 1
m17*m29*0.1
nodelay
--
0
PMID: 17449723 MyD88 does, however, bind IRAK-1, which contains a TRAF6-binding site, leading to NF-{kappa}B activation. PMID: 17449723 This phosphorylation is required for the activation of a pathway culminating in transactivation by the NF-{kappa}B subunit p65 via phosphorylation on serine 536.
p18
p18
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c50 : 1
stoichiometry:c51 : 1
stoichiometry:c52 : 1
m155666*m367*0.1
nodelay
--
0
PMID: 17449723 By an as-yet-unknown mechanism, Btk is activated following LPS stimulation of the cell.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c56 : 1
stoichiometry:c57 : 1
stoichiometry:c58 : 1
m31*m3964*0.1
nodelay
--
0
PMID: 17449723 Mal recruits MyD88 to TLR2 and TLR4, and TRAM recruits TRIF to TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c7 : 1
stoichiometry:c8 : 1
stoichiometry:c9 : 1
m155666*m3961*0.1
nodelay
--
0
PMID: 17449723 In cases of infection, LPS, derived from gram-negative bacteria, binds TLR4 dimers.
p20
p20
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c53 : 1
stoichiometry:c55 : 1
stoichiometry:c54 : 1
m367*m32*0.1
nodelay
--
0
PMID: 17449723, 16439361 Gray et al. [27 ] demonstrated that Mal can be tyrosine-phosphorylated at residues 86 and 187 by Bruton¡Çs tyrosine kinase (Btk) following activation of TLR2 and TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c59 : 1
stoichiometry:c166 : 1
stoichiometry:c60 : 1
m30*m29*0.1
nodelay
--
0
PMID: 17449723, 16439361 Gray et al. [27 ] demonstrated that Mal can be tyrosine-phosphorylated at residues 86 and 187 by Bruton¡Çs tyrosine kinase (Btk) following activation of TLR2 and TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c61 : 1
stoichiometry:c63 : 1
stoichiometry:c62 : 1
m33*m1906*0.1
nodelay
--
0
PMID: 17449723 SOCS-1 recognizes a proline, glutamic acid, serine, and threonine-rich area domain (PEST) in Mal, N-terminal to its TIR domain and subsequently, targets Mal for degradation by the addition of ubiquitin to lysine side-chains at amino acid positions 15 and 16. PMID: 17449723 Phospho-Mal is recognized by the ubiquitin ligase SOCS-1 (whose expression also increases in response to LPS).
p23
p23
cso30:i:ME_GeneExpression
cso30:i:CC_Nucleoplasm
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c64 : 1
stoichiometry:c65 : 1
m155666*0.1
nodelay
--
0
PMID: 17449723 Phospho-Mal is recognized by the ubiquitin ligase SOCS-1 (whose expression also increases in response to LPS).
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c66 : 1
stoichiometry:c67 : 1
stoichiometry:c68 : 1
m36*m34*0.1
nodelay
--
0
PMID: 17449723 SOCS-1 uses its E3 ligase activity to attach ubiquitin residues to Mal.
p25
p25
cso30:i:ME_ProteasomeDegradation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c69 : 1
stoichiometry:c70 : 1
stoichiometry:c71 : 1
stoichiometry:c141 : 1
stoichiometry:c142 : 1
stoichiometry:c143 : 1
stoichiometry:c144 : 1
stoichiometry:c145 : 1
stoichiometry:c146 : 1
m35*0.1
nodelay
--
0
PMID: 17449723 This ubiquitination step targets Mal for degradation by the 26S proteasome.Mal is removed from the membrane. MyD88 can no longer interact directly with TLR4 and also leaves the membrane.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c72 : 1
stoichiometry:c73 : 1
stoichiometry:c74 : 1
m43675*m32*0.1
nodelay
--
0
PMID: 17449723 Mal recruits MyD88 to TLR2 and TLR4, and TRAM recruits TRIF to TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c75 : 1
stoichiometry:c76 : 1
stoichiometry:c77 : 1
m1572*m37*0.1
nodelay
--
0
PMID: 17449723 Mal recruits MyD88 to TLR2 and TLR4, and TRAM recruits TRIF to TLR4.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c80 : 1
stoichiometry:c119 : 1
stoichiometry:c79 : 1
m11*m47*0.1
nodelay
--
0
PMID: 17449723 Mal recruits MyD88 to TLR2 and TLR4, and TRAM recruits TRIF to TLR4. PMID: 17449723 TRAM is myristoylated in its N-terminus and becomes attached to the membrane in association with TLR4.
p29
p29
cso30:i:ME_Translation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c113 : 1
stoichiometry:c118 : 1
stoichiometry:c112 : 1
m93309*m19324*0.1
nodelay
--
0
PMID: 17449723, 16166516 The effect of TRIF here is to induce TNF-{alpha} production via activation of IRF3, with TNF-{alpha} acting in an autocrine manner to induce the late activation of NF-{kappa}B.
p3
p3
cso30:i:ME_Binding
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c4 : 1
stoichiometry:c5 : 1
stoichiometry:c161 : 1
stoichiometry:c6 : 1
m290229*m43675*m71*0.1
nodelay
--
0
PMID: 17449723 i) Mal is synthesized and produced and ii) binds PIP2 in the plasma membrane via its PIP2-binding domain. PMID: 17449723, 10589680 It was also shown that the localization of Mal to the plasma membrane by PIP2 binding is dependent on the ¦Â2-integrin CD11b in macrophages and also on the GTPase ADP ribosylation factor 6 (ARF6), which regulates production of PIP2 via activation of the enzyme PI-5K.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c81 : 1
stoichiometry:c193 : 1
stoichiometry:c164 : 1
stoichiometry:c82 : 1
m18998*m39*0.1
nodelay
--
0
PMID: 17449723 Mal recruits MyD88 to TLR2 and TLR4, and TRAM recruits TRIF to TLR4. PMID: 17449723 This leads to the recruitment of TRIF to the TRAM/TLR4 complex. PMID: 17449723 It was also shown that treatment of cells with LPS enhances SARM expression, and it has been speculated that following TLR4 activation, SARM levels increase in cells and eventually bind TRIF to limit the LPS-driven response.
p31
p31
cso30:i:ME_Phosphorylation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c11 : 1
stoichiometry:c12 : 1
stoichiometry:c83 : 1
m38*m17*0.1
nodelay
--
0
PMID: 17449723 The MyD88 pathway leads to activation of the transcription factors NF-{kappa}B, IRF1, IRF5, and IRF7.
p32
p32
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c84 : 1
stoichiometry:c98 : 1
stoichiometry:c85 : 1
m970*m29*0.1
nodelay
--
0
PMID: 17449723 The MyD88 pathway leads to activation of the transcription factors NF-{kappa}B, IRF1, IRF5, and IRF7.
p33
p33
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c86 : 1
stoichiometry:c97 : 1
stoichiometry:c87 : 1
m979*m29*0.1
nodelay
--
0
PMID: 17449723 The MyD88 pathway leads to activation of the transcription factors NF-{kappa}B, IRF1, IRF5, and IRF7.
p34
p34
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c88 : 1
stoichiometry:c96 : 1
stoichiometry:c89 : 1
m980*m29*0.1
nodelay
--
0
PMID: 17449723 The MyD88 pathway leads to activation of the transcription factors NF-{kappa}B, IRF1, IRF5, and IRF7.
p35
p35
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c90 : 1
stoichiometry:c99 : 1
stoichiometry:c91 : 1
m970*m38*0.1
nodelay
--
0
PMID: 17449723 The MyD88 pathway leads to activation of the transcription factors NF-{kappa}B, IRF1, IRF5, and IRF7.
p36
p36
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c92 : 1
stoichiometry:c101 : 1
stoichiometry:c93 : 1
m979*m38*0.1
nodelay
--
0
PMID: 17449723 The MyD88 pathway leads to activation of the transcription factors NF-{kappa}B, IRF1, IRF5, and IRF7.
p37
p37
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c94 : 1
stoichiometry:c102 : 1
stoichiometry:c95 : 1
m980*m38*0.1
nodelay
--
0
PMID: 17449723 The MyD88 pathway leads to activation of the transcription factors NF-{kappa}B, IRF1, IRF5, and IRF7.
p38
p38
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c104 : 1
stoichiometry:c108 : 1
stoichiometry:c105 : 1
m20*m19*0.1
nodelay
--
0
PMID: 17449723, 12609980 Following the discovery that activation of NF-{kappa}B, p38 MAPK, and JNK was impaired in MyD88-deficient cells in response to all TLRs, except in the case of TLR3.
p39
p39
cso30:i:ME_GeneExpression
cso30:i:CC_Nucleoplasm
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c117 : 1
stoichiometry:c111 : 1
m19324*0.1
nodelay
--
0
PMID: 17449723, 16166516 The effect of TRIF here is to induce TNF-{alpha} production via activation of IRF3, with TNF-{alpha} acting in an autocrine manner to induce the late activation of NF-{kappa}B.
p4
p4
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c100 : 1
stoichiometry:c110 : 1
stoichiometry:c103 : 1
m21*m19*0.1
nodelay
--
0
PMID: 17449723, 12609980 Following the discovery that activation of NF-{kappa}B, p38 MAPK, and JNK was impaired in MyD88-deficient cells in response to all TLRs, except in the case of TLR3.
p40
p40
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c106 : 1
stoichiometry:c109 : 1
stoichiometry:c107 : 1
m69*m19*0.1
nodelay
--
0
PMID: 17449723, 12609980 Following the discovery that activation of NF-{kappa}B, p38 MAPK, and JNK was impaired in MyD88-deficient cells in response to all TLRs, except in the case of TLR3.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c10 : 1
stoichiometry:c78 : 1
m19005*0.1
nodelay
--
0
PMID: 17449723 TRAM is myristoylated in its N-terminus and becomes attached to the membrane in association with TLR4.
p42
p42
cso30:i:ME_Phosphorylation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c114 : 1
stoichiometry:c116 : 1
stoichiometry:c115 : 1
m42*m46*0.1
nodelay
--
0
PMID: 17449723 TRIF then interacts with downstream signaling molecules such as Tank-binding kinase-1, which phosphorylates and activates the transcription factor IRF3.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c120 : 1
stoichiometry:c121 : 1
stoichiometry:c122 : 1
m3902*m40*0.1
nodelay
--
0
PMID: 17449723 TRIF then interacts with downstream signaling molecules such as Tank-binding kinase-1, which phosphorylates and activates the transcription factor IRF3.
p44
p44
cso30:i:ME_Binding
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c123 : 1
stoichiometry:c124 : 1
stoichiometry:c127 : 1
stoichiometry:c128 : 1
m40*m183*m48*0.1
nodelay
--
0
PMID: 17449723 TRIF also interacts with TRAF6 and receptor-interacting protein-1, which brings about the activation of NF-{kappa}B.
p45
p45
cso30:i:ME_Phosphorylation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c125 : 1
stoichiometry:c129 : 1
stoichiometry:c126 : 1
m17*m49*0.1
nodelay
--
0
PMID: 17449723 TRIF also interacts with TRAF6 and receptor-interacting protein-1, which brings about the activation of NF-{kappa}B.
p46
p46
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c130 : 1
stoichiometry:c138 : 1
stoichiometry:c156 : 1
stoichiometry:c131 : 1
m1629*m155666*m66*0.1
nodelay
--
0
PMID: 17449723 By an as-yet-unknown mechanism, PKC{epsilon} is activated in response to LPS. PMID: 17449723, 11696589, 9601053 The kinase responsible for phosphorylation of TRAM was found to be protein kinase C {epsilon} (PKC{epsilon}), which was known to have a role in LPS signaling [36 ], and its activation by other signaling molecules such as diacyglycerol [37 ] may again provide another level of control in the LPS response.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c134 : 1
stoichiometry:c132 : 1
stoichiometry:c133 : 1
m63*m46*0.1
nodelay
--
0
PMID: 17449723 PKC{epsilon} phosphorylates TRAM at serine 16.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c135 : 1
stoichiometry:c137 : 1
stoichiometry:c136 : 1
m49*m63*0.1
nodelay
--
0
PMID: 17449723 PKC{epsilon} phosphorylates TRAM at serine 16.
p49
p49
cso30:i:ME_Dissociation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c139 : 1
stoichiometry:c147 : 1
stoichiometry:c149 : 1
stoichiometry:c151 : 1
stoichiometry:c171 : 1
m64*0.1
nodelay
--
0
PMID: 17449723 This phosphorylation event may also cause TRAM to leave the membrane. viii) With TRAM depleted from the membrane, TRIF no longer interacts with TLR4 and also leaves the membrane. This disrupts the signaling pathway and limits the response to LPS. PMID: 17449723 TLR4 is also degraded at this point.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c13 : 1
stoichiometry:c15 : 1
stoichiometry:c14 : 1
m6*m15*0.1
nodelay
--
0
PMID: 17449723 Upon activation, TLRs interact intracellularly with these adaptor proteins via TIR domains, and the adaptor proteins then recruit and activate downstream molecules such as IL-1R-associated kinases (IRAKs) and TNF-receptor-associated factor-6 (TRAF6), which then amplify the signal.
p50
p50
cso30:i:ME_Dissociation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c140 : 1
stoichiometry:c148 : 1
stoichiometry:c150 : 1
stoichiometry:c152 : 1
stoichiometry:c153 : 1
stoichiometry:c172 : 1
m65*0.1
nodelay
--
0
PMID: 17449723 This phosphorylation event may also cause TRAM to leave the membrane. viii) With TRAM depleted from the membrane, TRIF no longer interacts with TLR4 and also leaves the membrane. This disrupts the signaling pathway and limits the response to LPS. PMID: 17449723 TLR4 is also degraded at this point.
p51
p51
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c154 : 1
stoichiometry:c155 : 1
stoichiometry:c157 : 1
m2142*m158*0.1
nodelay
--
0
PMID: 17449723 ARF6 is activated by integrins.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c158 : 1
stoichiometry:c160 : 1
stoichiometry:c159 : 1
m68*m67*0.1
nodelay
--
0
PMID: 17449723, 10589680 It was also shown that the localization of Mal to the plasma membrane by PIP2 binding is dependent on the ¦Â2-integrin CD11b in macrophages and also on the GTPase ADP ribosylation factor 6 (ARF6), which regulates production of PIP2 via activation of the enzyme PI-5K.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c162 : 1
stoichiometry:c163 : 1
m70*0.1
nodelay
--
0
PMID: 17449723, 10589680 It was also shown that the localization of Mal to the plasma membrane by PIP2 binding is dependent on the ¦Â2-integrin CD11b in macrophages and also on the GTPase ADP ribosylation factor 6 (ARF6), which regulates production of PIP2 via activation of the enzyme PI-5K.
p55
p55
cso30:i:ME_Phosphorylation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c168 : 1
stoichiometry:c170 : 1
stoichiometry:c169 : 1
m17*m230*0.1
nodelay
--
0
PMID: 17449723, 16166516 The effect of TRIF here is to induce TNF-{alpha} production via activation of IRF3, with TNF-{alpha} acting in an autocrine manner to induce the late activation of NF-{kappa}B.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c173 : 1
stoichiometry:c174 : 1
stoichiometry:c175 : 1
m75*m74*0.1
nodelay
--
0
PMID: 17449723, 16807108 These proteins, similar to TLRs, respond to PAMPs, usually in the cytoplasmic environment.
p57
p57
cso30:i:ME_UnknownActivation
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c176 : 1
stoichiometry:c178 : 1
stoichiometry:c177 : 1
m1765*m76*0.1
nodelay
--
0
PMID: 17449723 Caspase-1 must be activated in inflammasomes, which consist of another group of an innate pathogen sensor, nucleotide oligomerization domain-like receptors (NLRs), including the proteins Nalp1, Nalp3, and Ipaf.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c179 : 1
stoichiometry:c180 : 1
stoichiometry:c181 : 1
m43675*m77*0.1
nodelay
--
0
PMID: 17449723, 17360653 Another interesting feature of Mal is its recently discovered ability to interact with caspase-1 [32 ], which is an important inflammatory caspase, responsible for cleavage of pro-IL-1beta into a catalytically active form secreted by cells.
p59
p59
cso30:i:ME_ProteinCleavage
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c182 : 1
stoichiometry:c184 : 1
stoichiometry:c183 : 1
m4012*m78*0.1
nodelay
--
0
PMID: 17449723, 17360653 Another interesting feature of Mal is its recently discovered ability to interact with caspase-1 [32 ], which is an important inflammatory caspase, responsible for cleavage of pro-IL-1beta into a catalytically active form secreted by cells.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c16 : 1
stoichiometry:c17 : 1
stoichiometry:c18 : 1
m16*m184*0.1
nodelay
--
0
PMID: 17449723 Upon activation, TLRs interact intracellularly with these adaptor proteins via TIR domains, and the adaptor proteins then recruit and activate downstream molecules such as IL-1R-associated kinases (IRAKs) and TNF-receptor-associated factor-6 (TRAF6), which then amplify the signal.
p60
p60
cso30:i:ME_Binding
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c185 : 1
stoichiometry:c186 : 1
stoichiometry:c188 : 1
stoichiometry:c187 : 1
m18998*m79*m155666*0.1
nodelay
--
0
PMID: 17449723 The SARM protein interacts with TRIF, and this interaction requires its TIR domain. PMID: 17449723 This interaction is weak in untreated cells but is enhanced by LPS or dsRNA treatment.
p61
p61
cso30:i:ME_Binding
cso30:i:CC_Cytosol
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c189 : 1
stoichiometry:c190 : 1
stoichiometry:c191 : 1
stoichiometry:c192 : 1
m119368*m79*m18998*0.1
nodelay
--
0
PMID: 17449723 The SARM protein interacts with TRIF, and this interaction requires its TIR domain. PMID: 17449723 This interaction is weak in untreated cells but is enhanced by LPS or dsRNA treatment.
p62
p62
cso30:i:ME_GeneExpression
cso30:i:CC_Nucleoplasm
--
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c195 : 1
stoichiometry:c194 : 1
m155666*0.1
nodelay
--
0
PMID: 17449723 It was also shown that treatment of cells with LPS enhances SARM expression, and it has been speculated that following TLR4 activation, SARM levels increase in cells and eventually bind TRIF to limit the LPS-driven response.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c19 : 1
stoichiometry:c196 : 1
stoichiometry:c20 : 1
m183*m18*0.1
nodelay
--
0
PMID: 17449723 Upon activation, TLRs interact intracellularly with these adaptor proteins via TIR domains, and the adaptor proteins then recruit and activate downstream molecules such as IL-1R-associated kinases (IRAKs) and TNF-receptor-associated factor-6 (TRAF6), which then amplify the signal.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c21 : 1
stoichiometry:c26 : 1
stoichiometry:c25 : 1
m17*m19*0.1
nodelay
--
0
PMID: 17449723, 16698941 TLR signaling ultimately results in the activation of transcription factors such as NF-{kappa}B and IFN regulatory factors (IRFs), which promote the transcription of proinflammatory cytokines and other proteins that promote host defense.
--
and
mass
coefficient1:0.1
coefficient2:1.0
stoichiometry:c22 : 1
stoichiometry:c23 : 1
stoichiometry:c24 : 1
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PMID: 17449723, 16698941 TLR signaling ultimately results in the activation of transcription factors such as NF-{kappa}B and IFN regulatory factors (IRFs), which promote the transcription of proinflammatory cytokines and other proteins that promote host defense.
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