1. Regulation of Human Immune System by TMED7
Christ’s College ERSS
4th September 2012
Ardi Liaunardy-Jopeace
Prof. Nick Gay Lab
Department of Biochemistry

2. What is Biochemistry?

3. PROTEINS!

4. Immunity Outside Inside Physical and chemical barriers
e.g. skin, mucous membrane
Innate immune response
Adaptive immune response
Vaccination
Antibodies
Specific
Germs!!! Bleurgh..
Outside
Inside

5. Immunity Outside Inside Innate immune response
Physical and chemical barriers
e.g. skin, mucus membrane
Innate immune response
Non-specific
Acute response
Requires pattern-recognition receptors (PRRs)
Adaptive immune response
Germs!!! Bleurgh..
Outside
Inside

6. Innate Immunity
Outside of cell
Cell surface

7. Members of Toll-like receptor family in human
Kanzler et. al., Nature Medicine Vol. 13, No. 5, May 2007

8. Birth of proteins DNA RNA Protein Mature proteins
Golgi apparatus
Rough Endoplasmic Reticulum
Mature proteins
Nucleus
DNA RNA Protein

9. Message is relayed involving many proteins
Receptor signalling
Information arrival
Signal
Receptor, e.g. TLR4
Information detection
Message is relayed involving many proteins
Output: production of certain proteins in response to the signal
Nucleus

10. TLR4 signalling There are two distinct pathways Inflammation
Mal-MyD88
NF-κB transcription factor
Inflammation
TLR4
TRAM-TRIF
IRF3 transcription factor
Antiviral response
Interferon-sensitive response element
Plasma membrane
Endosomes

11. Toll-like receptor 4 signalling
Cell surface
LPS
TLR4
CD14
MD2
Early endosome
Antiviral response
Inflammation

12. How do you control TLR4 activity?
Pre-activation
Post-activation
TMED7?
TMED7?
Control their production?
Control their activity once they have been produced and activated?

13. What is TMED7? GOLD domain Coiled-coil region for binding to itself
Membrane
The tail contains a ‘post code’ information

14. Results

15. TMED7 makes a physical contact with TLR4
Surface where the contact is made
GOLD domain
Coiled-coil region for binding to itself
Membrane

16. How does TMED7 control TLR4?

17. Experiment #1 TMED7 sends TLR4 to the correct place

18. Inflammation

19. Inflammation

20. Inflammation

21. Antiviral

22. 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

23. Hypothesis
Protein production
Message relay process
TMED7?
TMED7?

24. Experiment #2

25. GOLD domain + coiled coil domain (CC) GOLD domain (GOLD)
Endosome/ ER lumen
Cytoplasm
GOLD domain + coiled coil domain (CC)
GOLD domain (GOLD)
Full length (TMED7)

26. Antiviral

27. Inflammation

28. Inflammation

29. Inflammation response
Without signal from LPS

30. Hypothesis
Protein production
Message relay process 

31. ???
Postcode-less TMED7 (CC)

32. 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

33. 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

34. 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?

35. Thanks for not falling asleep! Questions?