Regulation of Human Immune System by TMED7 Christ’s College ERSS 4 th September 2012 Ardi Liaunardy-Jopeace Prof. Nick Gay Lab Department of Biochemistry
Mar 31, 2015
Regulation of Human Immune System by TMED7
Christ’s College ERSS4th September 2012
Ardi Liaunardy-JopeaceProf. Nick Gay Lab
Department of Biochemistry
What is Biochemistry?
PROTEINS!
Immunity
Germs!!! Bleurgh..
Innate immune response
Adaptive immune response• Vaccination• Antibodies• Specific
Outside Inside
Physical and chemical barrierse.g. skin, mucous membrane
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
Innate ImmunityOutside of cell
Cell surface
Members of Toll-like receptor family in human
Kanzler et. al., Nature Medicine Vol. 13, No. 5, May 2007
Birth of proteins
Nucleus
DNA RNA Protein
Golgi apparatus
Rough Endoplasmic Reticulum
Mature proteins
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
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
11
Toll-like receptor 4 signalling
TLR4
CD14MD2
Early endosome
Antiviral response
Inflammation
Cell surface
LPS
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
What is TMED7?
GOLD domain
Coiled-coil region for binding to itself
Membrane
The tail contains a ‘post code’ information
Results
TMED7 makes a physical contact with TLR4
GOLD domain
Coiled-coil region for binding to itself
Membrane
Surface where the contact is made
How does TMED7 control TLR4?
Experiment #1TMED7 sends TLR4 to the correct place
Inflammation
Inflammation
Inflammation
Antiviral
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
TMED7?
TMED7?
HypothesisProtein production Message relay process
Experiment #2
Endosome/ ER lumen
Cytoplasm
Full length (TMED7)
GOLD domain + coiled coil domain (CC)
GOLD domain (GOLD)
Antiviral
Inflammation
Inflammation
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
Hypothesis
Protein production Message relay process
???
Postcode-less TMED7 (CC)
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
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
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?
Thanks for not falling asleep!
Questions?