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Dr Andrew MacDonald

Dr Andrew Macdonald is an RCUK funded Academic research fellow in systems approaches to cell signalling and gene expression, in the Institute of Molecular and Cellular Biology. Andrew obtained both his B.Sc. (Medical Microbiology, 1998) and P.hD. (Molecular Virology, 2001) from the University of Leeds. After Post-Doctoral training in the laboratory of Prof. Mark Harris, working on the cell biology of Hepatitis C virus, Andrew obtained a highly competitive Career Development Fellowship position at the MRC Protein Phosphorylation Unit, University of Dundee, to work on the role of MAP-kinases in T cell development and function. Andrew re-joined the University of Leeds in December 2006 to instigate an investigation into the cell biology of the innate immune response to virus infection.

Research Areas: Structural studies on immune signaling proteins

Molecular and Structural Biology of Innate Immunity
A key aspect of the innate immune response is the synthesis and secretion of interferons (IFN), which exhibit anti-viral and immunomodulatory functions. Research in my laboratory focuses on how the cell responds to infection by viruses and the signalling pathways that are required to up-regulate transcription of the IFN gene (Figure 1). In addition, we are interested in how pathogens try to prevent activation of these signalling pathways and how this correlates with disease.

dsRNA helicases are intracellular anti-viral sentinels.
Our lab is interested in two novel RNA helicases that have been shown to contain anti-viral properties, RIG-I and Mda-5. Although there has been considerable interest surrounding these enzymes, little is known regarding their function and substrate specificity. Both RIG-I and Mda-5 contain two copies of a small protein domain, termed a CARD domain, which is known to mediate protein-protein interaction between the helicases and an adaptor protein termed MAVS (Figure 2). Using reporter assays we have shown that both RIG-I and Mda-5 are able to activate transcription of the IFN gene, although there appears to be tighter regulation of RIG-I (Figure 2). We are currently pursuing proteomic screens in an effort to identify binding proteins and shed light on the activation mechanisms of these crucial proteins.

Structural analysis of CARD domains.
In collaboration with Dr Thomas Edwards (Astbury Centre, Leeds), we are actively seeking to determine the three-dimensional crystal structure of the CARD domains from RIG-I and Mda-5. In an effort to further understand the mechanisms of interaction, we are attempting to co-crystallise these CARD domains in complex with the MAVS adaptor protein and ubiquitin (Figure 3). It is hoped that these studies will shed light on how RIG-I and Mda-5 transmit an anti-viral signalling cascade by allowing rational mutagenesis.

Regulation of TBK1 and IKK epsilon- kinases with the key to transcription.
Induction of IFN by both RIG-I and Mda-5 pathways requires the TANK-binding kinase (TBK1) and its homologue IKKe, two non-canonical members of the IKK family that have been shown to primarily phosphorylate interferon regulatory factors 3 and 7 (IRF3 and IRF7). In comparison with other IKK family members, little is known about TBK1 or IKKe, including the mechanisms by which these kinases are activated. Using a combination of proteomics and yeast two hybrid assays we have made substantial progress towards producing a working model for how these kinase are activated. We are continuing with our efforts and our current work is focussing on the role of the small protein ubiquitin in regulating these signalling pathways.

Funding.
RCUK and The University of Leeds.

Collaborators.
I have active collaborations with groups in the UK, Finland and the USA.

Publications from the last 5 years:

No publication data available in ULPD (University of Leeds Publications Database)

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