2010 Annual Report - Institute for Molecular Bioscience - University ...

imb annual report 2010
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ROHAN TEASDALE
ENDOSOMAL DYNAMICS: REGULATED
ENDOCYTOSIS, HOST-PATHOGEN INTERACTIONS
AND PROTEIN TRAFFICKING
THE ENDOSOMAL/LYSOSOMAL
system of mammalian cells is a highly
dynamic organelle, and the trafficking
pathways within the endosomal system
are fundamental for a wide variety of key
cellular processes. My group is developing
cellular and computational approaches
to identify novel mammalian proteins
associated with the endosomal system.
The regulated movement of membrane
receptors and ligands between the cell
surface and intracellular compartments
is vital to many cellular operations,
including communication between cells
and their environment. A major current
focus of the group is the characterisation
of the mammalian retromer complex. My
research into defining the composition of a
mammalian endosomal protein complex,
termed the retromer, has made major
contributions to its recent emergence as a
central critical regulator of early endosome
protein trafficking. I discovered a novel core
retromer complex, defined by a second
VPS26 paralog, and originally discovered
multiple members of the sorting nexin
family that associate with retromer. Our
recent work on sorting nexin 5 (SNX5)
represents the first report of the association
of sorting nexins and retromer proteins with
macropinosomes. This study involved the
application of high-quality live cell imaging
to visualise the maturation process of
macropinosomes. Based on our findings
of a dynamic association of GFP-SNX5
with macropinosomes, we have detected
a transient and very extensive tubular
network that is essential to the maturation
of the macropinosome in macrophages.
Macropinocytosis is a regulated form
of endocytosis that mediates the nonselective
uptake of extracellular material.
Macropinocytosis is highly relevant to
many aspects of both normal cell function
and disease with particular importance in
tumour progression and metastasis and
in many infectious diseases. Recently I
have focused on the establishment of a
systems biology approach to examine the
biogenesis of macropinosomes. I have
established a number of functional assays
to quantify the kinetics of formation and
fate of individual macropinosomes.
Numerous infectious pathogens exploit
macropinocytosis to invade the host.
Characterisation of pathogen entry
pathways is essential for understanding
infectious diseases but has also proven to
be a powerful tool for gaining insight into
normal cellular processes. We are currently
investigating the molecular details of these
pathways and how they are modulated in
response to infection with Salmonella, a
leading cause of human gastroenteritis.
Currently we have established High
Content Screening (HCS) approaches,
combined with high-throughput RNA.
RESEARCH PROJECTS
• Host-Pathogen interactions during
Salmonella infection
• Maintaining and updating LOCATE:
A Protein Subcellular Localisation
Database – http://locate.imb.uq.edu.au
• Developing computational approaches
to analyse image and real-time
microscopy data
• Studying endosome dynamics,
macropinocytosis and retromer
• Systems biology of the mammalian
endosome
• Establishment of High Content
Screening (HCS) applications including
high throughput RNA-interference
(RNAi) screens
KEY PUBLICATIONS
Kerr, M.C., Wang, J.T.H., Castro, N.,
Hamilton, N.A., Town, L., Brown, D.L.,
Meunier, F.A., Brown, N.F., Stow, J.L.,
and Teasdale, R.D. (2010). Inhibition of
the PtdIns(5) kinase PIKfyve disrupts
intracellular replication of Salmonella.
EMBO Journal 29: 1331-1347.
Wang, J.T., Kerr, M.C., Karunaratne, S.,
Jeanes, A., Yap, A.S., and Teasdale,
R.D. (2010). The SNX-PX-BAR family
in macropinocytosis: the regulation of
macropinosome formation by SNX-PX-
BAR proteins. PLoS One 5: e13763.
Kerr, M.C., and Teasdale, R.D. (2009).
Defining Macropinocytosis. Traffic 10:
364-371.
Hamilton, N., and Teasdale, R.D.
(2008). Visualizing and Clustering High
Throughput Sub-cellular Localization
Imaging. BMC Bioinformatics 9: 81.
Sprenger, J., Fink, J.L., Karunaratne, S.,
Hanson, K., Hamilton, N., and Teasdale,
R.D. (2007). LOCATE: A Mammalian
Protein Subcellular Localization Database.
Nucleic Acids Research 36(Database
issue): D230-233.
LAB MEMBERS
Research Officers: Dr Markus Kerr, Dr
Andrea Bugarcic, Dr Michael Hanzal-
Bayer, Dr David Liebl
Research Assistants: Seetha
Karunaratne, John Griffin, Zhe Yang,
Shara Close
PhD Students: Josefine Sprenger, Jack
Wang