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

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

What is Biochemistry?


Regulation of human immune system by tmed7

PROTEINS!


Immunity

Immunity

Physical and chemical barriers

e.g. skin, mucous membrane

  • Adaptive immune response

  • Vaccination

  • Antibodies

  • Specific

  • Innate immune response

Germs!!! Bleurgh..

Outside

Inside


Immunity1

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

Innate Immunity

Outside of cell

Cell surface


Members of toll like receptor family in human

Members of Toll-like receptor family in human

Kanzler et. al., Nature Medicine Vol. 13, No. 5, May 2007


Birth of proteins

Birth of proteins

Mature proteins

Rough Endoplasmic Reticulum

Golgi apparatus

Nucleus

DNA RNA Protein


Receptor signalling

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

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


Regulation of human immune system by tmed7

Toll-like receptor 4 signalling

CD14

LPS

MD2

Cell surface

TLR4

Early endosome

Inflammation

Antiviral response


Regulation of human immune system by tmed7

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

What is TMED7?

GOLD domain

Coiled-coil region for binding to itself

Membrane

The tail contains a ‘post code’ information


Results

Results


Tmed7 makes a physical contact with tlr4

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

How does TMED7 control TLR4?


Experiment 1 tmed7 sends tlr4 to the correct place

Experiment #1TMED7 sends TLR4 to the correct place


Regulation of human immune system by tmed7

Inflammation


Regulation of human immune system by tmed7

Inflammation


Regulation of human immune system by tmed7

Inflammation


Regulation of human immune system by tmed7

Antiviral


Summary

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


Regulation of human immune system by tmed7

Hypothesis

Protein production

Message relay process

TMED7?

TMED7?


Experiment 2

Experiment #2


Regulation of human immune system by tmed7

Endosome/ ER lumen

Cytoplasm

GOLD domain + coiled coil domain (CC)

GOLD domain (GOLD)

Full length (TMED7)


Regulation of human immune system by tmed7

Antiviral


Regulation of human immune system by tmed7

Inflammation


Regulation of human immune system by tmed7

Inflammation


Regulation of human immune system by tmed7

Inflammation response

Without signal from LPS


Regulation of human immune system by tmed7

Hypothesis

Protein production

Message relay process




Regulation of human immune system by tmed7

???

Postcode-less TMED7 (CC)


Summary1

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

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


Relevance1

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

Thanks for not falling asleep!Questions?


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