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?