Bacterial and viral infections activate the signal transduction networks that regulate the innate immune system, and trigger the production of inflammatory mediators to combat the pathogens. Understanding these signalling networks is important, not just because it may lead to the development of improved drugs to fight infection, but also because failure to control the production of inflammatory mediators causes major global diseases, such as arthritis, asthma, colitis, fibrosis, lupus, psoriasis and sepsis.
My group studies the activation and output of these signalling networks, and we also aim to identify which components are attractive drug targets for the treatment of disease. Another focus is to understand the interplay between protein phosphorylation and protein ubiquitylation in regulating the innate immune system, which we tackle by using a range of state-of-the-art techniques that include molecular, cellular and chemical biology, protein chemistry, mass spectrometry and mouse genetics.
Recently we have made the surprising discovery that hybrid ubiquitin chains (containing more than one linkage type) play a critical role in regulating the activation of the protein kinases TAK1 and IKKβ in several innate immune signalling networks. We also discovered unexpectedly that the TRAF6 and Pellino E3 ubiquitin ligases operate redundantly to produce Lys63-linked ubiquitin chains in the MyD88 signalling pathway, and that the essential roles of TRAF6 are independent of its E3 ligase function. Other projects are focussed on the role TRAF6 in regulating the adaptive immune system and on the dissection of the TLR3 signalling network, which is critical for protection against Herpes Simplex Virus Encephalitis, a devastating disease of the Central Nervous System in young children.