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Regulation of Myd88 Dependent Signalling Flashcards

1
Q

Name 2 UBP which mutations in are linked to immune disease

A

NEMO

Optineurin (OPTN)

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2
Q

Name an E3 ligase which when mutated is linked to immune disease

A

LUBAC

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3
Q

Name 2 protein kinases which when mutated is linked to immune disease

A

IRAK4

TBK1

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4
Q

How does Myd88 stimulate NF-kappaB and MAPK signalling?

A 
Binds to TLR using Mal
IRAK4 is recruited 
IRAK1 and 2 is recruited 
Traf6 causes the activation of Tak1 
NF-kappaB and MAPK signalling
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5
Q

How does Trif cause IRF3 signalling?

A

Trif binds to TLR using TRAM -> Traf3 -> TBK1 -> IRF3

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6
Q

What 2 receptor families does Myd88 bind to?

A

IL-1 receptor family

TLR

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7
Q

What does IL-1 receptor bind to?

A

IL-1 family members:

  • IL-1
  • IL-18
  • IL-33
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8
Q

What do TLRs bind to?

A

PAMPs

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9
Q

What are the 2 domains in TLRs?

A

Leucine rich repeat domain

TIR domain

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10
Q

What TLRs couple to Myd88?

A

All except TLR3

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11
Q

What TLR2 and TLR4 require to recruit Myd88?

A

2nd adaptor, Mal

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12
Q

What can TLR3 and TLR4 couple with?

A

Trif

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13
Q

How is Trif recruitment to TLR4 mediated?

A

Using Tram

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14
Q

What TLRs are expressed on the cell surface?

A 
TLR5 
TLR1 
TLR2 
TLR6 
TLR4
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15
Q

What TLRs are expressed on endosomes?

A

TLR3
TLR7
TLR8
TLR9

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16
Q

What is the ligand for TLR5?

A

Flagellin

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17
Q

What is the ligand for TLR1/2?

A

Triacylated Lipopeptides

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18
Q

What is the ligand for TLR2/6?

A

Diacyclated lipopeptides

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19
Q

What is the ligand for TLR4?

A

LPS

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20
Q

What is the ligand for TLR3?

A

dsRNA

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21
Q

What is the ligand for TLR7/8?

A

ssRNA

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22
Q

What is the ligand for TLR9?

A

CpG DNA

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23
Q

How is Mal recruited to the TLR?

A

Mal has a TIR domain which binds to TLR TIR domain

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24
Q

How does Myd88 bind to Mal?

A

Through the TIR domains

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25
Q

How does IRAK4 bind to Mys88?

A

Through the death domains

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26
Q

How does IRAK4 recruit IRAK1/2?

A

Through its death domain

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27
Q

In what form does Myd88 bind to Mal?

A

As an oligomer

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28
Q

What are IRAK1 and 2?

A

Pseudosubstrates

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29
Q

How is TAK1 activated?

A

by the addition of K63 linked chains

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30
Q

What are TRAF proteins?

A

Tumour necrosis factor receptor (TNFR)-associated factors

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31
Q

how many isoforms of TRAF are there?

A

6

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32
Q

Apart from TRAF1, what domain do all of the TRAFs have?

A

A RING domain

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33
Q

What is the RING domain important for?

A

Function:

  • Some are E3 Ub ligases
  • In some cases may be for scaffolding
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34
Q

What is the function of TRAF5?

A

Negative regulator:

- inhibits TLR and IL-6`

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35
Q

What is the function of TRAF6?

A

IL-1/ TLR signalling

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36
Q

What is the function of TRAF1 and 2?

A

Act downstream of the TNR receptor

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37
Q

What is the function of TRAF3?

A

important downstream of CD30

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38
Q

What is the function of TRAF4?

A

involved in neurotophin signalling in the brain

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39
Q

What causes the addition of the K63 linked chains to the Myd88osome?

A

E2 ligase Ubc13 and E3 ligases Pelino 1 and 2 and Traf6

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40
Q

What is the Myd88osome?

A

TLR + Myd88 + IRAK4 + IRAK1/2

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41
Q

Where do the K63 linkages attach?

A

IRAK1/2

Traf6

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42
Q

How do you remove downstream signalling of Myd88?

A

Have to remove both Pelino 1 and 2 and Traf6

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43
Q

What is the Tak1 complex?

A

It binds to Tab2/3 (only one at a time) and Tab1

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44
Q

What do Tab2/3 bind to?

A

The C-terminal NFZ domain binds to K63 linked PolyUb chains

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45
Q

What is the N-terminal domain of Tak1?

A

Protein kinase domain

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46
Q

How is Tak1 activated?

A

by binding to Tab1

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47
Q

What is the N terminal domain of Tab1?

A

N-terminal pseudophosphate domain

48
Q

What part of Tab1 binds to Tak1?

A

The C terminal domain

49
Q

What is the function of Tak1?

A

Can be a MAP3K for p38 and JNK MAPK pathways

Actives IKK which can activate NF-kappaB and ERK1/2 MAPK cascade

50
Q

How does Enteropathogenic E. Coli target Tab2 and 3 to suppress the immune system?

A

They inject NIeE into cells via a Type III secretion system -> Methylates Tab2 and 3 -> disrupts NFZ domain and prevents Ub binding -> inhibition of NF-kappaB

51
Q

How do Enteropathogenic E.coli methylate Tab2 and 3?

A

NIeE encodes a cysteine methylase

52
Q

What polyUb chain binds onto the K63 linked chain?

53
Q

What causes the formation of M1 chain?

A

Potentially E2 ligase UbcH7

E3 ligase Lubac

54
Q

What are the 3 protein in LUBAC?

A

Sharpin
HOIL
HOIP

55
Q

Where is the E3 catalytic site in LUBAC?

A

In the Rcat RING domain of HOIP

56
Q

What does mutations in the Rcat RING domain of HOIP cause?

A

Blocks M1 formation downstream of Myd88

57
Q

How does LUBAC interact with the PolyUb chain?

A

Through the NFZ domains

58
Q

What do mutations in HOIL cause in humans?

A

Increases susceptibility to bacterial infection and autoinflammatory disorders

59
Q

What do mutations in Sharpin cause in humans?

A

Chronic proliferative dermatitis

60
Q

Where does Nemo bind?

A

to the M1 PolyUb chain

61
Q

How is IKK recruited to the complex?

A

Via the NEMO subunit

62
Q

What 2 subunits of IKK bind to Nemo?

A

IKKalpha and beta

63
Q

How does Tak1 induce MAPK and NF-kappaB signalling?

A

Through phosphorylating and activating IKKbeta

64
Q

Does do NEMO bind to M1 PolyUb chains?

A

Through its UBAN domain

65
Q

What does NF-kappaB function as?

A

A homo or heterodimer

66
Q

What is NF-kappaB?

A

A transcription factor

67
Q

How does NF-kappaB function as a transcription factor?

A

Through the RHD domains

68
Q

What are inhibitors of NF-kappaB?

A

IkappaBalpha and IkappaBbeta

69
Q

How do IkappaB proteins act as inhibitors?

A

Through their Rel subunits to keep NF-kappaB in the cytoplasm

70
Q

What family mediates the activation of NF-kappaB?

A

The IKK family:

  • NEMO
  • IKKalpha
  • IKKbeta
71
Q

What pathways can be used to activate NF-kappaB?

A

Canonical
Non-canonical
Atypical
IKK independent

72
Q

What does the canonical pathway work downstream of?

73
Q

How does the IKK complex activate NF-kappaB?

A

It phosphorylates IkappaB which is bound to NF-kappaB dimer in the cytoplasm -> NF-kappaB moves to the nucleus and promotes transcription

74
Q

How is IkappaBalpha targeted for degradation?

A

It is phosphorylated on two serine residues on the D-S-G-X-X-S motif -> recognised by F-box protein b-TcRP -> recruitment of SCF complex -> IkappaBalpha ubiquitylation on K21 and K22

75
Q

What happens if the 2 serine residues in D-S-G-X-X-S in IkappaBalpha are mutated?

A

Prevents degradation of IkappaBalpha

76
Q

What happens if K21 and K22 of IkappaBalpha are mutated?

A

stabilises IkappaBalpha

77
Q

What are the components of the SCF complex?

A 
Substrate 
beta-TcRP
Skp1 
Cul1 
Rbx1
E2
78
Q

What is beta-TcRP?

A

A receptor

79
Q

What is Skp1?

A

An adaptor

80
Q

What is Cul1?

A

A scaffold

81
Q

What is Rbx1?

A

A RING domain

82
Q

What is the SCF complex?

A

A multi component E2 ligase complex

83
Q

How is the SCF complex activated?

A

By the addition of Nedd8 to Cul1 -> conformational change -> frees the E2 and moves it into position to interact with the substrate

84
Q

What is the E2 in the case of SCF binding to IkappaB?

85
Q

What Ub linkage does Cdc34 induce on IkappaB?

86
Q

What is the role of E2 ligase UbcH5?

A

To add the first Ub onto IkappaB

87
Q

What happens after the first Ub has been added?

A

UbcH5 is removed and Cdc34 (E2) is added and forms the polyUb chain

88
Q

What does the K48 polyUb chain on IkappaB induce?

A

IkappaB to undergo proteasomal degradation

89
Q

How do TLRs and IL-1Rs induce MAPK signalling?

A

Instead of using Raf, they use Tpl2

90
Q

In unstimulated cells, what does Tpl2 exist as?

A

An inactive complex with Abin2 and p105

91
Q

How does IL-1Rs induce Tpl2 activation?

A

Tak1 phosphorylates and activates IKKbeta -> phosphorylates p105 -> promotes K48 linked polyUb to p105 -> targeted for degradation -> Tpl2/Abin1/p105 complex dissociates -> Tpl2 is released -> ERK1/2 activation

92
Q

Why does Tpl2 exist as an inactive complex?

A

It stabilises it and maintains its expression in the cell

93
Q

What does Abin1 KO prevent?

A

Prevents ERK1/2 activation since Tpl2 is destabilised and not present in the cells

94
Q

What domain does Abin1 have?

A

A UBAN domain which can bind K63 linked chains and M1 linked chains

95
Q

Is Abin1 binding to K63 and M1 linked chains essential for ERK1/2 signalling?

96
Q

What are upstream of JNK?

A

MKK4 and 7

97
Q

What activates MKK4 and 7?

98
Q

What is upstream of p38?

A

MKK3, 6 and 4

99
Q

what activates MKK3 and 6?

A

Tak1 and Tpl2

100
Q

How do you prove the requirement for Tak1?

A

Overexpression studies
Tak1 inhibitors
Loss of function studies

101
Q

what is the issue with Tak1 inhibitors?

A

they often inhibit other kinases too

102
Q

What happens in you KO Tab2/3 OR Tak1 OR Tab1?

A

Embryonic lethality

103
Q

Due to embryonic lethality, how is this studied?

A

Fibroblasts can be isolated from mouse embryos

104
Q

What happens in you KO Tak1?

A

Prevents IL-1 induced JNK activation

105
Q

What happens in you KO Tab1?

A

Does not prevent IL-1 induced JNK activation

106
Q

What happens in you KO Tab2?

A

Does not prevent IL-1 induced JNK activation

107
Q

Why may KO of Tab2 induce this phenotype?

A

Tab3 could compensate

108
Q

What happens if you KO Tak1 in bone marrow derived macrophages?

A

They will die during M-CSF induced differentiation

109
Q

What happens if you KO Tak1 in myeloid cells?

A

Increased levels of ROS

110
Q

What is Ask1?

A

A member of the MAP3K family

111
Q

How does ROS induce p38 MAPK activation?

A

TLR4 activation -> ROS increase -> Ask1 activation -> activate p38 MAPK

112
Q

Is Tak1 involved in peritoneal macrophages?

113
Q

How does Tak1 KO effect B cells?

A

Stops TLR induced MAPK activation in B cells

114
Q

Is Tak2 and 3 required in macrophages?

115
Q

Is Tak2 and 3 required in B cells?

116
Q

What is needed to completely block Tak1 signalling?

A

Loss of Tab1, 2 and 3

Advanced Cell Signalling (12 decks)

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