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

What is Biochemistry?

PROTEINS!

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

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

Innate Immunity Outside 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 DNA RNA Protein Mature proteins Golgi apparatus Rough Endoplasmic Reticulum Mature proteins Nucleus DNA RNA Protein

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

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

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

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?

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 Surface where the contact is made GOLD domain Coiled-coil region for binding to itself Membrane

How does TMED7 control TLR4?

Experiment #1 TMED7 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

Hypothesis Protein production Message relay process TMED7? TMED7?

Experiment #2

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)

Antiviral

Inflammation

Inflammation

Inflammation response Without 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?