Bacterial and viral infections activate the signal transduction networks that regulate the innate immune system, and trigger the production of inflammatory mediators to combat these 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 several unexpected discoveries. First, that hybrid ubiquitin chains containing several linkage types play critical roles in regulating innate immune signalling networks; second that the essential roles of TRAF6 in initiating innate immune signalling are independent of its E3 ligase activity; third that the HOIL-1 component of the Linear Ubiquitin Assembly Complex (LUBAC) is a remarkable E3 ligase that attaches ubiquitin to serine and threonine residues in proteins by forming ester bonds. Current projects are focused on understanding how the HOIL-1 E3 ligase controls innate immune signalling, why the SIK family of protein kinases are required for pro-inflammatory cytokine production, and why the TRAF6 E3 ligase restricts T cell activation. We are also studying how the ubiquitin-binding protein ABIN1 restricts activation of the MyD88-IRAK4-IRAK1 signaling axis to prevent lupus, and dissecting the TLR3 signaling network, which is critical for protection against Herpes Simplex Virus Encephalitis, a devasting disease of the central nervous system in young children.
