| Staff Listings |
Professor Trevor Lithgow
ARC Federation Fellow
 |
Tel: +61-3-9902 9217
Fax: +61-3-9905 3726
Office: Room 252, Level 2, Building 76
Reception: Building 77, Science Technology Research & Innovation Precinct
Email: trevor.lithgow@monash.edu
A major global issue is the rise of antibiotic-resistance in bacterial pathogens. In response, new drug targets need to be identified and new vaccines need to be developed. Fundamental aspects of bacterial cell biology need to be understood if we are to take creative approaches to defeating these "new" bacterial pathogens. Our lab works on protein targeting; how proteins are transported to their correct sub-cellular location. My interests are particularly focused at how bacterial proteins are targeted to outer membranes: the targeting machinery is an excellent target for new drugs and the surface-exposed nature of the machinery means that it could serve as a basis in new vaccine strategies.
Work in my laboratory falls into two broad themes : (i) the evolution of protein transport machines and (ii) the mechanism by which protein transporters function. We are particularly interested in comparative analysis of the protein transport machines found in bacteria and in mitochondria; the two are related through evolution and each provides clues to understanding the mechanism by which proteins are transported to outer membranes.
We are members of the NHMRC Program in Cellular Microbiology and we work together with other members of the Monash Unit for Host-Pathogen Molecular Biology. Scholarship support is available to new PhD students. PhD postgraduate scholarships are available for Australian citizens or permanent residents with a H1 Honours degree. We have positions for international students: applicants are advised to check the Graduate studies web pages for information on entry requirements, tuition fee, and scholarships prior to application.
The Lithgow Lab Alumni can be found here.
Evolution of Protein Transport Machines
Mitochondria in our cells evolved from an intracellular bacterium that initially served to provide ATP to the earliest eukaryotic cells. Our work shows that this bacterium provided the protein transport pathways that were essential to the development of the first eukaryotes.
Figure 1. Protein targeting to mitochondria. In my laboratory, the mitochondrial protein import pathway has been characterized in detail in the yeast Saccharomyces cerevisiae. While the basic components of the pathway are conserved across the board, fascinating differences exist in organisms like Trypanosoma brucei, Giardia inestinalis and microsporidia. We have established assays to study protein transport in organisms such as these and used the differences to determine the fundamental aspects of the protein transport pathways.
Link to the above article published in Science:
Mechanisms of Protein Transport and Assembly
Much of our current research aims at characterizing the function of protein transport machines in bacteria - using knowledge of the mitochondrial and other systems, and expertise in genetics, biochemistry and cell biology. We are working to understand how bacterial pathogens assemble protein transport machines in their outer membranes, and how these function to target "effector" proteins into human cells.
Figure 2. Targeting and assembly of proteins into outer membranes. The mitochondrial “SAM complex” evolved from the bacterial “BAM complex”. We have several projects aimed at understanding how these protein transport machines assemble beta-barrel proteins into bacterial (and mitochondrial) outer membranes.
New Projects
Honours and postgraduate projects employ a broad range of techniques in molecular biology, genetics, computer science and cell biology. New projects on offer include:
- Characterization of the targeting lipids and proteins into the outer membrane of Klebsiella pneumoniae. This project is in collaboration with Professor Dick Strugnell (University of Melbourne). A combination of bioinformatics, mass spectrometry, atomic force microscopy and biochemical assays will be used for identification and characterization of the transporters responsible for assembly of the outer membrane and capsule.
- Characterization of the Type 2 and 3 secretion systems (T2SS, T3SS) in EPEC (pathogenic Escherichia coli) and Salmonella spp. This project is in collaboration with Associate Professor Rohan Teasdale (University of Queensland) and Professor Liz Hartland (University of Melbourne). A combination of bioinformatics, high-throughput RNAi and biochemical assays will be used for identification and characterization of the transporters.
- Defining how integral membrane proteins are assembled into the mitochondrial outer membrane. This project will make use of yeast genetics and biochemical assays. Good evidence suggests a conserved mechanism is behind the assembly of tail-anchored proteins such as the Bcl-2 family and proteins with more complicated topologies such as beta-barrels.
- Using yeast genetics and systems biology approaches to screen for novel factors involved in the first steps of protein transport to mitochondria. Protein transport is subject to tight regulation in "time and space". Yeast provides a model to understand the regulatory mechanisms, which are at play in humans and other animals too.
Lab Members
Back row (L to R): Victoria Hewitt, Miguel Shingu-Vasquez, Chaille Webb, Hsin-Hui Shen
Front row (L to R): Trevor Lithgow, Matthew Belousoff, Denisse Leyton, Rhys Dunstan, Eva Heinz
Some Recent Publications from the Lithgow Lab
- Selkrig J, Mosbahi K, Webb CT, Belousoff MJ, Perry AJ, Wells TJ, Morris F, Leyton DL, Totsika M, Phan MD, Celik N, Kelly M, Oates C, Hartland EL, Robins-Browne RM, Ramarathinam SH, Purcell AW, Schembri MA, Strugnell RA, Henderson IR, Walker D & Lithgow T. (2012) Discovery of an archetypal protein transport system in bacterial outer membrane. Nat. Struct. Mol. Biol. (in press).
- Dolezal P, Aili M, Tong J, Jiang JH, Marobbio CM, Lee SF, Schuelein R, Belluzzo S, Binova E, Mousnier A, Frankel G, Giannuzzi G, Palmieri F, Gabriel K, Naderer T, Hartland EL & Lithgow T. (2012) Legionella pneumophila secretes a mitochondrial carrier protein during infection. PLoS Pathog. 8:e1002459
- Alcock F, Clements A, Webb C & Lithgow T. (2010) Evolution. Tinkering inside the organelle. Science 327: 649-50 Link to reprint
- Dolezal P, Likić V, Tachezy J & Lithgow T. (2006) Evolution of the molecular machines for protein import into mitochondria. Science 313: 314-8.
- Clements A, Bursac D, Gatsos X, Perry AJ, Civciristov S, Celik N, Likić VA, Poggio S, Jacobs-Wagner C, Strugnell RA & Lithgow T. (2009) The reducible complexity of a mitochondrial molecular machine. Proc. Natl. Acad. Sci. 106: 15791-5
- Gatsos X, Perry AJ, Anwari K, Dolezal P, Wolynec PP, Likić VA, Purcell AW, Buchanan SK & Lithgow T. (2008) Protein secretion and outer membrane assembly in alphaproteobacteria. FEMS Microbiol. Rev. 32, 995-1009
- Chacinska A, Koehler CM, Milenkovic D, Lithgow T & Pfanner N. (2009) Importing mitochondrial proteins: machineries and mechanisms. Cell 138: 628-44
NHMRC Program in Cellular Microbiology
