Regulation of human immune system by tmed7
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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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Regulation of Human Immune System by TMED7

Christ’s College ERSS

4th September 2012

ArdiLiaunardy-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

  • Vaccination

  • Antibodies

  • Specific

  • Innate immune response

Germs!!! Bleurgh..

Outside

Inside


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


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

Mature proteins

Rough Endoplasmic Reticulum

Golgi apparatus

Nucleus

DNA RNA Protein


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

TLR4

Mal-MyD88

NF-κB transcription factor

Inflammation

TLR4

TRAM-TRIF

IRF3 transcription factor

Antiviral response

Plasma membrane

Endosomes


Toll-like receptor 4 signalling

CD14

LPS

MD2

Cell surface

TLR4

Early endosome

Inflammation

Antiviral response


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?


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

Surface where the contact is made

Membrane


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


Hypothesis

Protein production

Message relay process

TMED7?

TMED7?


Experiment #2


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?


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