Understanding the innate immune system is essential for the development of new therapies for the treatment of microbial infection, the management of autoimmune disorders and the provision of protective immunity via vaccination. My group investigates two members of the intracellular NOD-like receptor family, NOD1 and NOD2. These proteins are activated by fragments of bacterial peptidoglycan; γ-D-glutamyl-meso-diaminopimelic acid for NOD1 and muramyl dipeptide for NOD2.
Ligand recognition stimulates receptor oligomerisation and initiates a signalling cascade that ultimately leads to the upregulation of a pro-inflammatory immune response. NOD1 and NOD2 are both associated with a predisposition to inflammatory disorders. The best characterised of these is the role of NOD2 single nucleotide polymorphisms in the inflammatory bowel disorder Crohn’s Disease.
Our work is specifically aimed at developing an understanding of how these proteins recognise their ligands and how they propagate signalling within the cell. We are investigating the molecular basis of protein-protein interactions particularly between NOD1 and NOD2 and their protein cofactors and adaptor proteins. We are also looking at the impact of polymorphisms on the function of the receptors. To achieve these aims we are using a variety of functional assays and biochemical and biophysical techniques. We hope to ultimately utilise x-ray crystallography to determine the molecular structure of these proteins.
Lab members: Joseph Boyle, Sophie Gooch, Rhiannon Parkhouse
1. Man SM , Tourlomousis P, Hopkins L, Monie T, Fitzgerald K, Bryant C (2013) Salmonella infection induces recruitment of Caspase-8 to the inflammasome to modulate interleukin-1Β production. J Immunol. 2013 Nov 15; 191(10):5239-46. PMID: 24123685
2. Boyle JP, Mayle S, Parkhouse R, Monie TP (2013) Comparative Genomic and Sequence Analysis Provides Insight into the Molecular Functionality of NOD1 and NOD2. Front Immunol. 2013 Oct 7:4:317 PMID: 2410948
3. Parkhouse R, Ebong I-O, Robinson CV, Monie TP (2013) The N-terminal region of the human autophagy protein ATG16L1 contains a domain that folds into a helical structure consistent with formation of a coiled-coil. PLoS One. 2013 Sep 24;8(9):e76237 PMID: 24086718
4. Herre J, Gronlund H, Brookes H, Waggoner L, Gooch S, Murton B, Opaleye N, Fitzgerald K, Gay N, Monie TP*, Bryant C*(2013). Allergens as Immuno-Modulatory Proteins: the cat dander protein FelD1 enhances Toll-like receptor activation by lipid ligands. J Immunol. 2013 Aug 15;191(4):1529-35 *Joint corresponding authors. PMID: 23878318
5. Joseph P Boyle, Clare E Bryant and Tom P Monie (2013). Cell Swelling and the NLRP3 Inflammasome. Immunity. 2013 Mar 21;38(3):399
6. Monie TP*. (2013) NLR activation takes a direct route. Trends Biochem Sci. 2013 Mar;38(3):131-9
7. Yereddi NR, Cusdin FS, Namadurai S, Packman LC, Monie TP, Slayny P, Clare JJ, Powel AJ, Jackson AP. (2013) The immunoglobulin domain of the sodium channel b3-subunit contains a surface-localized disulfide bond that is required for homophilic binding. FASEB J. Feb;27(2):568-80
8. Mo J-Y, Boyle JP, Howard CB, Monie TP, Davis BK, Duncan JA. (2012) NOD2 mediated pathogen sensing is mediated by direct binding to muramyl dipeptide and ATP. J Biol Chem. 2012 Jun 29;287(27):23057-67
9. Boyle JP and Monie TP. (2012) Computational Analysis Predicts the Kaposi’s Sarcoma-Associated Herpesvirus Tegument Protein ORF63 to be Alpha Helical. Proteins. 2012 Aug;80(8):2063-70
10. Bryant CE and Monie TP. (2012) Mice, men and the relatives: cross-species studies underpin innate immunity. Open Biol. 2012 2:120015