7 Members of Toll-like receptor family in human Kanzler et. al., Nature Medicine Vol. 13, No. 5, May 2007
8 Birth of proteins DNA RNA Protein Mature proteins Golgi apparatusRough Endoplasmic ReticulumMature proteinsNucleusDNA RNA Protein
9 Message is relayed involving many proteins Receptor signallingInformation arrivalSignalReceptor, e.g. TLR4Information detectionMessage is relayed involving many proteinsOutput: production of certain proteins in response to the signalNucleus
10 TLR4 signalling There are two distinct pathways Inflammation Mal-MyD88NF-κB transcription factorInflammationTLR4TRAM-TRIFIRF3 transcription factorAntiviral responseInterferon-sensitive response elementPlasma membraneEndosomes
22 SummaryIncreasing TMED7 on its own can elevate both the inflammation and antiviral responses without signal from LPSBut this has very little/ no effects on LPS- stimulated activations of both pathwaysHypothesis: TMED7 sends TLR4 to the correct places, therefore increases the availability of TLR4
32 SummaryTLR4 is important for detecting attacking pathogens by recognising bacterial componentsSignal from LPS leads to rapid innate immune responses such as inflammation, redness, feverThis activity can be controlled pre- or post- LPS signalTMED7 makes a physical contact with TLR4TMED7 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 immunityAdaptive immunity
34 Relevance? Inflammation versus antiviral responses How much inflammation do we need?Septic shockAutoimmune diseasesExploiting the pathways so we can get a more favourable outcome?