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Regulation of Human Immune System by TMED7

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. What is Biochemistry?. PROTEINS!. Immunity. Physical and chemical barriers e.g. skin, mucous membrane. Adaptive immune response

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Regulation of Human Immune System by TMED7

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

  2. What is Biochemistry?

  3. PROTEINS!

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

  5. Immunity • Innate immune response • Non-specific • Acute response • Requires pattern-recognition receptors (PRRs) Physical and chemical barriers e.g. skin, mucus membrane 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 Mature proteins Rough Endoplasmic Reticulum Golgi apparatus Nucleus DNA RNA Protein

  9. 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 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 CD14 LPS MD2 Cell surface TLR4 Early endosome Inflammation Antiviral response

  12. Pre-activation Post-activation How do you control TLR4 activity? 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 GOLD domain Coiled-coil region for binding to itself Surface where the contact is made Membrane

  16. How does TMED7 control TLR4?

  17. Experiment #1TMED7 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. 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?

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