Lecture 26: TLRs Flashcards
What is TL4 ?
LPS sensor
What is the C3H/HeJ mouse ?
Mutation inTIR domain of TLR4 that converts a conserved proline resiue to a histidine mice resistant to LPS lethality
What is the TIR domain made up of ?
- 3 boxes of conserved residues set in core sequence of 130-160 aa with intervening variable residues
What is the structure of TIR domain ?
Central 5-stranded parallel B-sheet surrounded by 5-helices on each side
What is the only TLR that heterodimerises ?
TLR2
What can TLR2 heterodimerise with ?
TLR1 and TLR6
What does TLR1 and TLR2 sense ?
Triacyl lipopeptides
What does TLR2 and TLR6 sense ?
Diaceylated lipopeptides
What does TLR5 sense ?
Flagellin
What does TLR4 sense ?
LPS
What does TLR3 sense ?
Double stranded RNA
What does TLR7 sense ?
Single stranded RNA
What does TLR8 sense ?
Single stranded RNA
What does TLR9 sense ?
CpG DNA
How does sensing of TLRs occur ?
Binding of ligand to ligand recognition receptor drivers dimerisation of partner TLRs
What is the response of TLR signalling ?
Dimerisation of receptors brings TIR domains together. Adapter proteins are then recruited
What does MyD88 do ?
Initiates signalling to NFkappaB
What does TRIF do ?
Initiates signalling to IRFs
What is the bridge MyD88 uses ?
Mal bridge
What is the bridge TRIF uses ?
TRAM
What is the accessory protein of TLR4 ?
MD2
What does the MD2-LPS interaction trigger ?
TLR4 homodimers
How does TLR4 initiate TIR signalling ?
Intracellularly
In TLR2 what does direct interactions with lipopeptide ligand drive ?
Heterodimerisation
What does TLR2 use for signalling ?
Mal - MyD88/NFkappaB
Why does MAL sensitise ?
For optimal NFkappaB
Where is TLR3 found ?
On endosomal membrane
What does TLR3 recruit ?
TRIF
What does TRIF drive ?
Signalling to IRF3 via TRAF3
What does TLR3-TRIF activate ?
NFkappaB
What is the interaction between TLR4 and TLR3 ?
TLR4 translocates to endosomal membrane via TRAM to engage TRAF3
Where is TLR9 found ?
Endosomal membrane
What is TLR9 a sensor of ?
Unmethylated CpG- DNA
What regulates the localisation of TLR9 ?
UNC93B
What does TLR9 recruit ?
MYD88
What do synthetic oligodeoxynucleotides do ?
Bind different sites increasing signal
What is imiquiomod ?
Synthetic TLR7 agoinist - melanoma
What does TLR5 trigger ?
MyD88
What does TLR7 and 8 trigger ?
MyD88
Where is TLR10 not functional ?
Mice
What are the TLR effector functions ?
- MyD88/NFkappaB signalling
- TRIF/IRF signalling
- Activates MAP kinases
- Alter phagocytic capacity
5.Maturation of cytokine - Enhances expression of anti-microbial genes
What do TLR4-MAL/TRAM sorting adapter do ?
Get the signal to where it needs to be to drive specific effects
What do endosomal TLRs, chaperone proteins do ?
Get the receptor where it needs to be to encounter specific ligands
What preferentially engages TRAM/TRIF internalisation pathways ?
Co- receptor CD14
What helps the internalisation and delivery to endolysosome for TLR recognition uptake ?
Association of DNA with antibodies
What are NOD like receptors ?
Cytosolic proteins
What are NOD like receptors a sensor of ?
Breakdown products of PGN
What does NOD1 recognise ?
DAP
What does NOD2 recognise ?
MDP
What is the structure of NOD like receptor ?
- Leucine rich repeats
- Nucleotide binding domain
- CARD
What does the CARD-CARD interaction with RIP2 in NOD like receptors activate ?
NFkappaB and MAP-K
What does maturation to bio-active IL-1B require ?
Intracellular proteolytic cleavage by caspase 1
What are included in the families of inflammasomes ?
- NLRP1
- NLRP3
- NLRC4
- Caspase-11
- AIM 2
What is AIM2 ?
Cytosolic DNA binding protein
What does AIM2 have ?
- Hin domain
- PYD
What does AIM2 recruit ?
ASC
What is cGAS ?
Cytosolic enzyme
What does cGAS do in the presence of dsDNA ?
Generate 2* messenger cGAMP
What does cGAMP bind ?
STING on er
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
