Lecture 26: TLRs Flashcards

1
Q

What is TL4 ?

A

LPS sensor

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2
Q

What is the C3H/HeJ mouse ?

A

Mutation inTIR domain of TLR4 that converts a conserved proline resiue to a histidine mice resistant to LPS lethality

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3
Q

What is the TIR domain made up of ?

A
  1. 3 boxes of conserved residues set in core sequence of 130-160 aa with intervening variable residues
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4
Q

What is the structure of TIR domain ?

A

Central 5-stranded parallel B-sheet surrounded by 5-helices on each side

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5
Q

What is the only TLR that heterodimerises ?

A

TLR2

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6
Q

What can TLR2 heterodimerise with ?

A

TLR1 and TLR6

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7
Q

What does TLR1 and TLR2 sense ?

A

Triacyl lipopeptides

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8
Q

What does TLR2 and TLR6 sense ?

A

Diaceylated lipopeptides

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9
Q

What does TLR5 sense ?

A

Flagellin

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10
Q

What does TLR4 sense ?

A

LPS

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11
Q

What does TLR3 sense ?

A

Double stranded RNA

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12
Q

What does TLR7 sense ?

A

Single stranded RNA

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13
Q

What does TLR8 sense ?

A

Single stranded RNA

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14
Q

What does TLR9 sense ?

A

CpG DNA

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15
Q

How does sensing of TLRs occur ?

A

Binding of ligand to ligand recognition receptor drivers dimerisation of partner TLRs

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16
Q

What is the response of TLR signalling ?

A

Dimerisation of receptors brings TIR domains together. Adapter proteins are then recruited

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17
Q

What does MyD88 do ?

A

Initiates signalling to NFkappaB

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18
Q

What does TRIF do ?

A

Initiates signalling to IRFs

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19
Q

What is the bridge MyD88 uses ?

A

Mal bridge

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20
Q

What is the bridge TRIF uses ?

A

TRAM

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21
Q

What is the accessory protein of TLR4 ?

A

MD2

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22
Q

What does the MD2-LPS interaction trigger ?

A

TLR4 homodimers

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23
Q

How does TLR4 initiate TIR signalling ?

A

Intracellularly

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24
Q

In TLR2 what does direct interactions with lipopeptide ligand drive ?

A

Heterodimerisation

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25
What does TLR2 use for signalling ?
Mal - MyD88/NFkappaB
26
Why does MAL sensitise ?
For optimal NFkappaB
27
Where is TLR3 found ?
On endosomal membrane
28
What does TLR3 recruit ?
TRIF
29
What does TRIF drive ?
Signalling to IRF3 via TRAF3
30
What does TLR3-TRIF activate ?
NFkappaB
31
What is the interaction between TLR4 and TLR3 ?
TLR4 translocates to endosomal membrane via TRAM to engage TRAF3
32
Where is TLR9 found ?
Endosomal membrane
33
What is TLR9 a sensor of ?
Unmethylated CpG- DNA
34
What regulates the localisation of TLR9 ?
UNC93B
35
What does TLR9 recruit ?
MYD88
36
What do synthetic oligodeoxynucleotides do ?
Bind different sites increasing signal
37
What is imiquiomod ?
Synthetic TLR7 agoinist - melanoma
38
What does TLR5 trigger ?
MyD88
39
What does TLR7 and 8 trigger ?
MyD88
40
Where is TLR10 not functional ?
Mice
41
What are the TLR effector functions ?
1. MyD88/NFkappaB signalling 2. TRIF/IRF signalling 3. Activates MAP kinases 4. Alter phagocytic capacity 5.Maturation of cytokine 6. Enhances expression of anti-microbial genes
42
What do TLR4-MAL/TRAM sorting adapter do ?
Get the signal to where it needs to be to drive specific effects
43
What do endosomal TLRs, chaperone proteins do ?
Get the receptor where it needs to be to encounter specific ligands
44
What preferentially engages TRAM/TRIF internalisation pathways ?
Co- receptor CD14
45
What helps the internalisation and delivery to endolysosome for TLR recognition uptake ?
Association of DNA with antibodies
46
What are NOD like receptors ?
Cytosolic proteins
47
What are NOD like receptors a sensor of ?
Breakdown products of PGN
48
What does NOD1 recognise ?
DAP
49
What does NOD2 recognise ?
MDP
50
What is the structure of NOD like receptor ?
1. Leucine rich repeats 2. Nucleotide binding domain 3. CARD
51
What does the CARD-CARD interaction with RIP2 in NOD like receptors activate ?
NFkappaB and MAP-K
52
What does maturation to bio-active IL-1B require ?
Intracellular proteolytic cleavage by caspase 1
53
What are included in the families of inflammasomes ?
1. NLRP1 2. NLRP3 3. NLRC4 4. Caspase-11 5. AIM 2
54
What is AIM2 ?
Cytosolic DNA binding protein
55
What does AIM2 have ?
1. Hin domain 2. PYD
56
What does AIM2 recruit ?
ASC
57
What is cGAS ?
Cytosolic enzyme
58
What does cGAS do in the presence of dsDNA ?
Generate 2* messenger cGAMP
59
What does cGAMP bind ?
STING on er
60
What is the caveat of of cGAS ?
cGAS detects dsDNA but some microbial RNA can form DNA:RNA hybrids or be RT'd to generate dsNA intermediates sensed by cGAS -STING