Paul Gleeson
For more information on Paul and his research, visit his 'Find an Expert' page
STRAPA project: Intracellular trafficking and function of the membrane receptor FcRn which prolongs the serum half-life of novel therapeutic proteins
(A collaborative project with CSL)
Supervisor: Professor Paul Gleeson
The so-called neonatal IgG Fc receptor (FcRn) protects IgG and albumin from intracellular degradation and plays a critical role in prolonging the half-life of these serum proteins in adults. FcRn binds to the Fc domain of IgG, and also to albumin, in acidic endosomal compartments and then recycles bound ligands back to the cell surface for release into the circulation. Given these properties, there is considerable interest in exploiting the biology of FcRn to enhance the half-life of therapeutic proteins by the inclusion of FcRn binding sites, ie the Fc domain, on recombinant proteins.
Knowledge of the mechanism of FcRn recycling and intracellular ligand interaction is particularly important in attempts to increase the lifespan in serum of antibody-based drugs and recombinant serum proteins. This project, a collaboration with biotechnology company CSL (which is based in the Bio21 Institute), will involve analysis of the intracellular compartments where ligand-FcRn interactions occur and definition of the intracellular itinerary of FcRn. The studies will be conducted in cultured cells and genetically modified mice.
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Research in the Gleeson laboratory
Our laboratory uses a range of state-of-the-art techniques in cell biology, molecular biology and molecular immunology to investigate the following:
Membrane trafficking and protein sorting
Membrane trafficking underpins many physiological processes, including secretion, receptor signaling, phagocytosis, nutrient uptake, antigen processing and presentation, and neural networking. Membrane trafficking is also exploited by infectious organisms and toxins to gain entry into the cell. A focus of this laboratory is to understand the molecular basis of membrane and protein sorting in the secretory and endocytic pathways of mammalian cells. We use a range of interference RNA (RNAi)approaches to silence gene expression in both cells and whole animals to explore the role of trafficking pathways in defined physiological systems.
Membrane transport from the Golgi apparatus
The trans-Golgi network (TGN) is a major traffic hub. We have identified a family of small GTPase effectors called TGN golgins, which regulate specific transport pathways. Our laboratory has developed a microRNA-based approach to silence these golgins in vivo and explore their physiological function. For example, one of the golgins regulates the secretion of tumour necrosis factor- in activated macrophages. The specific silencing of trafficking machinery represents a novel strategy to block secretion of factors that promote inflammation.
Regulation of endosomal traffic
Macropinocytosis is a regulated form of endocytosis and is highly active in macrophages and dendritic cells (antigen presenting cells) where it is a major pathway for the capture of antigens. Despite the importance of this pathway, the molecular basis for the formation and maturation of macropinosomes is poorly defined.
Projects:
- Investigating role of golgins in transport of defined cargos
- Generation and analysis of transgenic mice expressing micro RNA to TGN golgins
- Defining the specific recruitment of golgins to the Golgi membranes
- Investigating the role of macropinocytosis in antigen uptake by macrophages.
Molecular immunology and autoimmunity
Autoimmune disease occurs when the immune system turns against the body’s own tissues resulting in immune-mediated destruction. Our objective is to understand the development of autoimmune diseases and the basis for the loss of immunological tolerance to self-antigens. A long term goal of this research is to develop molecular strategies for the treatment of autoimmune disorders.
Organ-specific autoimmune disease and immunological tolerance: The basis for the loss of immunological tolerance to self-antigens and the development of autoimmune diseases is poorly understood. Infections have long been considered as a potential trigger to cause autoimmunity. We have developed an experimental autoimmune gastritis as a powerful model of organ-specific autoimmunity. Our objectives are to define the mechanisms responsible for T cell tolerance to gastric autoantigens, to dissect the basis for the loss of tolerance to the dominant gastric autoantigen (H+/K+ ATPase) that leads to disease, and to define the specificity and mode of action of newly discovered immunoregulatory T cells. We have unique reagents including various transgenic lines and T cell receptors directed towards the primary autoantigen.
Projects:
- Investigating the impact of inflammatory mediators on disruption of T cell tolerance
- Defining gastric epitopes presented in the draining lymph node of the stomach
- Investigating the role of memory self-reactive T cells in driving autoimmune disease
Cell biology of acid-secreting epithelia
Acid secretion by gastric parietal cells is mediated by the tightly regulated H+/K+ ATPase, a proton pump present in the abundant specialised secretory membranes of these cells. Our goal is to apply a variety of genetic manipulation strategies to increase our understanding of the regulation of membrane transformation events that control acid secretion by parietal cells. To date, the coordinated events of membrane transport and proton pump activation are not well defined. We aim to understand the cell biology of acid secretion, including the development of the specialised secretory membranes, during parietal cell differentiation. This project is aimed at identifying the sorting signals of the cytoplasmic domain of the H+/K+ ATPase beta-subunit critical for the unique intracellular trafficking that occurs in parietal cells.
The laboratory
My laboratory is composed of postdoctoral scientists, postgraduates and undergraduates who work with a variety of biological systems and problems using a wide range of techniques. These techniques include cell transfection, construction and use of transgenic and knock-out mice, isolation of immune cells, many immunological techniques, immunohistochemistry, confocal microscopy, etc. The lab has close links with that of Ian van Driel of the Department of Biochemistry & Molecular Biology at the Bio21 Institute. Together, our two groups form a lively and interactive research team.
Lab personnel
Head
Professor Paul Gleeson
Research staff
Fiona Houghton, MSc (Senior research assistant)
Dr Dorothee Bourges (Post Doc)
Dr Jet Phey Lim (Post Doc)
Dr Sofia Nystrom (visiting scientist)
Graduate students
Cheryl Chia
Sarah Overall
Wei Hong Toh
Honours students
Kelly Zulkefli
Selected recent publications
- Kerr M.C., Lindsay M.R., Luetterforst R., Hamilton N., Simpson F., Parton R.G., Gleeson P.A., Teasdale R.D. (2006) 'Visualisation of macropinosome maturation by the recruitment of sorting nexins.' J Cell Sci 119, 3967-80.
- Derby MC, Zhao Lieu Z, Stow J, Goud B, Gleeson PA. (2007). 'The TGN golgin, GCC185, is required for endosome to Golgi transport and maintenance of Golgi structure'. Traffic, 8, 758–73
- Read S, Hogan T, Zwar T, Gleeson PA, van Driel IR. (2007) 'Prevention of autoimmune gastritis in mice requires extra-thymic T cell deletion.' Gastroenterology, 133(2), 547-58.
- Lieu ZZ, Lock JG, Hammond LA, La Gruta NL, Stow JL, Gleeson PA. (2008) ‘A trans-Golgi network golgin is required for the regulated secretion of TNFbeta in activated macrophages in vivo.' Proc Natl Acad Sci USA, 105, 3351-6.
- Purcell, AW, van Driel, IR and Gleeson, PA (2008) 'Impact of glycans on T-cell tolerance to glycosylated self-antigens.' Immunol Cell Biol, 86, 574-79.
- Houghton F, Chew PL, Lohedo S, Goud B and Gleeson PA (2009) 'The localization of the golgin, GCC185 is independent of Rab6A/A’ and Arl1.' Cell 138, 787-94.
- Gleeson PA and Goud, B (2010) 'TGN golgins, Rabs and cytoskeleton: Regulating the Golgi trafficking highways.' Trends Cell Biology, 20, 329-36.
- Chia, PZC and Gleeson, PA (2011) 'The regulation of endosome-to-Golgi retrograde transport by tethers and scaffolds.' Traffic, 12, 939-47
- Chia, PZC, Gasnereau, I, Lieu, ZZ and Gleeson, PA (2011). 'Rab-9 dependent retrograde transport and endosomal sorting of the endopeptidase, furin.' J Cell Sci, 124, 2401-13.
- Allen, S, Turner, SJ, Bourges, D, Gleeson, PA and van Driel, IR (2011). 'Shaping the T-cell repertoire in the periphery.' Immunol Cell Biol, 89, 60-9.
- Gasnereau, I, Herr, P, Chia, PZ, Basler, K and Gleeson, PA. (2011) 'Identification of an endocytosis motif in an intracellular loop of Wntless protein essential for its recycling and control of Wnt protein signaling.' J Biol Chem, 286, 43324-33.
- Chia, PZC and Gleeson, PA (2011) 'Intracellular trafficking of the beta-secretase and the processing of amyloid precursor protein.' IUBMB Life, 63 721-29.