Faculty of Medicine, Dentistry & Health Science Department of Biochemistry and Molecular Biology

Paul Gleeson

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.Diagram of secretory and endocytic pathways

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:

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:

Cell biology of acid-secreting epithelia

image of a parietal cell

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

Dr Zi Zhao (Robert) Lieu (Postdoctoral fellow)
Fiona Houghton (Senior research assistant)

Graduate students

Cheryl Chia
Priscilla Gunn
Jet Phey Lim
Sarah Overall

Honours students

Pradeep Balu

members of the Gleeson and van Driel research laboratories

Selected recent publications

  1. Gleeson PA, Lock J, Luke MR, Stow J. (2004) 'Domains of the TGN: Coats, tethers and G-proteins'. Traffic, 5, 315–26.
  2. Nguyen NV, Gleeson PA, Courtois-Coutry N, Caplan MJ, van Driel IR. (2004) 'Endocytosis of the H+/K+ ATPase from the apical plasma membrane is not required for regulation of gastric acid secretion'. Gastroenterology, 127, 145–54.
  3. van Driel IR, Read S, Zwar TD, Gleeson PA. (2005) Shaping the T cell repertoire to a bona fide autoantigen: lessons from autoimmune gastritis. Curr Opin Immunol, 17, 570–6.
  4. Zwar TD, Read S, van Driel IR, Gleeson PA. (2006) 'CD4+CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo'. J Immunol, 176, 1609–17.
  5. Kerr MC, Lindsay MR, Luetterforst R, Hamilton N, Simpson F, Parton RG, Gleeson PA, Teasdale RD. (2006) Visualisation of macropinosome maturation by the recruitment of sorting nexins. J Cell Sci, 119, 3967-80.
  6. 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.
  7. 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.
  8. 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.
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