Scheme: Royal Society Research Professorship
Organisation: University of Dundee
Dates: Oct 1984-Sep 2010
Summary: My research is aimed firstly at understanding how the innate immune system protects the body against infection by bacteria and viruses through the production of substances called pro-inflammatory cytokines and interferons, and secondly how the deregulation of this control system causes inflammatory and autoimmune diseases, such as arthritis, lupus, psoriasis and sepsis. In recent years it has become clear that innate immunity is controlled by the interplay of two different types of protein modification called “phosphorylation” and “ubiquitylation”, which are catalysed by different classes of enzymes termed “protein kinases” and “E3 ligases”, respectively.
Over the past year, my laboratory has made significant advances in understanding how two “protein kinases” called TBK1 and IKK? are switched on during infection and how they protect the body against infection. TBK1 and IKK? are members of a small subfamily of “protein kinases” that also includes IKK? and IKK?. We found that TBK1 and IKK? are switched on in two different ways during infection, one of which is controlled by IKK? and IKK?. We also discovered that, once activated, TBK1 and IKK? negatively regulate the catalytic activity of IKK? and IKK?, creating a feedback loop which ensures that the functions of all four enzymes are carefully coordinated with one another. Using improved drugs that switch off TBK1 and IKK? that were developed by our collaborators at Medical Research Council Technology, we discovered a novel role for TBK1 and IKK? in preventing the production of the anti-inflammatory cytokine interleukin 10 (IL-10). IL-10 plays a key role in preventing the over- production of several pro-inflammatory cytokines, such as TNF?, whose over-production is a major cause of septic shock and rheumatoid arthritis. These findings led us to demonstrate that the drugs that switch off TBK1 and IKK? prevent septic shock in mice, and we will now investigate whether they are also effective in models of rheumatoid arthritis.
Another major interest of my laboratory is in understanding how four related proteins, called NEMO, NRP, ABIN1 and ABIN2, control the innate immune system. These proteins share a feature that is needed for their attachment to particular types of “polyubiquitylated” proteins. The binding of such “polyubiquitin” chains to NEMO is known to be critical for the activation of IKK? and IKK?, but the roles of the other three proteins are poorly understood. We therefore replaced the normal forms of each protein with modified versions that are unable to interact with “polyubiquitin” chains. In last year’s report I mentioned that mice expressing a “polyubiquitin”-binding-defective mutant of ABIN1 develop a lupus-like autoimmune disease. We have now found that they have elevated levels of pro-inflammatory cytokines in the serum due to the overproduction of these substance by immune cells and elevated levels of antibodies, including pathogenic and auto-antibodies, that result from the over-production and hyoperactivation of a particular type of immune cell, called a B-cell. We have now been able to prevent these mice from developing autoimmune disease, by removing another protein called MyD88 which plays a crucial role in activating IKK? and IKK? during bacterial infection.
In summary, our results demonstrate that ABIN1 plays a key role in preventing the innate immune system from becoming too active and that the ability of ABIN1 to bind to “polyubiquitin” molecules is crucial for its function. The mouse line expressing a polyubiquitin-binding-defective form of ABIN1 is a new and defined model of autoimmune disease caused by a single change in one protein. This model should prove valuable for testing the effectiveness of new drugs for the treatment autoimmune disease, since another laboratory has recently reported that particular polymorphisms in ABIN1 that are present in the human population predispose to psoriasis, a type of autoimmune disease.