Regulation of Human Immune System by TMED7 Christs College ERSS 4 th September 2012 Ardi...
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![Page 1: Regulation of Human Immune System by TMED7 Christs College ERSS 4 th September 2012 Ardi Liaunardy-Jopeace Prof. Nick Gay Lab Department of Biochemistry.](https://reader036.fdocuments.in/reader036/viewer/2022070307/551a31c6550346545e8b4a63/html5/thumbnails/1.jpg)
Regulation of Human Immune System by TMED7
Christ’s College ERSS4th September 2012
Ardi Liaunardy-JopeaceProf. Nick Gay Lab
Department of Biochemistry
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What is Biochemistry?
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PROTEINS!
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Immunity
Germs!!! Bleurgh..
Innate immune response
Adaptive immune response• Vaccination• Antibodies• Specific
Outside Inside
Physical and chemical barrierse.g. skin, mucous membrane
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Immunity
Germs!!! Bleurgh..
Innate immune response• Non-specific• Acute response• Requires
pattern-recognition receptors (PRRs)
Adaptive immune response
Outside Inside
Physical and chemical barrierse.g. skin, mucus membrane
![Page 6: Regulation of Human Immune System by TMED7 Christs College ERSS 4 th September 2012 Ardi Liaunardy-Jopeace Prof. Nick Gay Lab Department of Biochemistry.](https://reader036.fdocuments.in/reader036/viewer/2022070307/551a31c6550346545e8b4a63/html5/thumbnails/6.jpg)
Innate ImmunityOutside of cell
Cell surface
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Members of Toll-like receptor family in human
Kanzler et. al., Nature Medicine Vol. 13, No. 5, May 2007
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Birth of proteins
Nucleus
DNA RNA Protein
Golgi apparatus
Rough Endoplasmic Reticulum
Mature proteins
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Receptor signallingSignal
Receptor, e.g. TLR4
Message is relayed involving many proteins
Nucleus Output: production of certain proteins in response to the signal
Information arrival
Information detection
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TLR4 signalling There are two distinct pathways
TLR4
Mal-MyD88
NF-κB transcription factor
Inflammation
TLR4
TRAM-TRIF
IRF3 transcription factor
Antiviral response
Plasma membrane Endosomes
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11
Toll-like receptor 4 signalling
TLR4
CD14MD2
Early endosome
Antiviral response
Inflammation
Cell surface
LPS
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How do you control TLR4 activity?
TMED7?
TMED7?
Control their production? Control their activity once they have been produced and activated?
Pre-activation Post-activation
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What is TMED7?
GOLD domain
Coiled-coil region for binding to itself
Membrane
The tail contains a ‘post code’ information
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Results
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TMED7 makes a physical contact with TLR4
GOLD domain
Coiled-coil region for binding to itself
Membrane
Surface where the contact is made
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How does TMED7 control TLR4?
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Experiment #1TMED7 sends TLR4 to the correct place
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Inflammation
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Inflammation
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Inflammation
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Antiviral
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Summary
• Increasing TMED7 on its own can elevate both the inflammation and antiviral responses without signal from LPS
• But this has very little/ no effects on LPS- stimulated activations of both pathways
• Hypothesis: TMED7 sends TLR4 to the correct places, therefore increases the availability of TLR4
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TMED7?
TMED7?
HypothesisProtein production Message relay process
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Experiment #2
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Endosome/ ER lumen
Cytoplasm
Full length (TMED7)
GOLD domain + coiled coil domain (CC)
GOLD domain (GOLD)
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Antiviral
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Inflammation
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Inflammation
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0 1 10 25 50 1000
20
40
60
80
100
120
TMED7CCGOLD
Amount of TMED7 or CC or GOLD
Resp
onse
Inflammation responseWithout signal from LPS
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Hypothesis
Protein production Message relay process
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???
Postcode-less TMED7 (CC)
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Summary
• TLR4 is important for detecting attacking pathogens by recognising bacterial components
• Signal from LPS leads to rapid innate immune responses such as inflammation, redness, fever
• This activity can be controlled pre- or post- LPS signal
• TMED7 makes a physical contact with TLR4• TMED7 acts as a birth controller/ chaperone of TLR4
and hence regulating TLR4’s activity pre-LPS signal
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Relevance?
• Innate immunity is a bridge to adaptive immunity
Hey, I just met you, and this is crazy. But here’s a germ, so kill it in the future, maybe?
Sure!
Innate immunity Adaptive immunity
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Relevance?
• Inflammation versus antiviral responses• How much inflammation do we need?– Septic shock– Autoimmune diseases
• Exploiting the pathways so we can get a more favourable outcome?
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Thanks for not falling asleep!
Questions?