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Ke Hu

Ke Hu

 

Assistant Professor

Ph.D., University of Pennsylvania, 2002
Postdoctoral Fellow, University of Pennsylvania, 2002-2003
Scripps Research Institute, 2003-2006

Program Affiliation: Molecular Biology & Genetics | Microbiology

Research Groups Affiliation: Cell Biology | Microbiology

Beckman Young investigator Award, 2008

Phone: 812/855-0166
Fax: 812/855-6082

Email Ke

Cytoskeletal Biogenesis of Apicomplexan Parasites

framework for organellar replication
Figure 1: Cell division in Apicomplexan parasites.  Apicomplexan parasites prepare for division by forming daughter cytoskeleton scaffolds within the mother. The de novo constructed daughter cytoskeletons (green) serve as scaffolds for organelle biogenesis and partitioning, while the mother cytoskeleton (red) remains intact for most of cell cycle.  The apicomplexan parasites differ in the number of daughters formed at each cell cycle, which varies from 2 (e.g. T. gondii as illustrated) to 2n(n>1) (e.g. P. falciparum) (The mitochondrion is not included in the drawing.).

biogenesis of scaffold structures
Figure 2. Drawings of T. gondii.  left: a longitudinal section of a dividing cell. Lobes of the dividing nucleus bordered by ER, Golgi (yellow)  are surrounded by the developing daughters' scaffolds (red).  Maternal and daughter conoids are shown in green, secretory organelles (rhoptries) in purple.  T. gondii has three membranes: a plasma membrane (black) and two additional layers (IMC, red) formed from a patchwork of flattened vesicles. middle:  semi-transparent view showing the 22 subpellicular MT (green) right: Enlarged view of the apical complex cytoskeleton, showing the conoid (green), preconoidal and polar rings (brown) and two intra-conoid MT (green).  The conoid is formed of 14 fibers of tubulin (not MT), 430 nm long, arranged in a left-handed spiral (Hu et al., JCB 2002)

cell biology cover PLoS cover
Figure 3. Left: CryoEM image of T. gondii cytoskeleton extracted by detergent (Hu et al., JCB 2002). Right: fluorescent image of T. gondii constructing daughter scaffolds within the mother cell. Cyan: YFP-α-Tubulin; yellow: mRFP-TgMORN1 (Hu, et al. PloS Pathogens, 2006)

Our lab is interested in understanding how cytoskeletal structures are organized and function in a group of fascinating eukaryotic parasites, the Apicomplexans. The phylum Apicomplexa contains ~ 5,000 species of obligate intracellular protozoan parasites, many of which are important human or animal pathogens, including Plasmodium falciparum, the most lethal cause of malaria that kills more than a million people every year, and Toxoplasma gondii,  the leading cause of congenital neurological defects in humans and a devastating opportunistic infection in immunocompromised patients.

The pathogenesis of these diseases is directly related to parasite replication, the understanding of which is thus crucial for developing effective therapies.  The replication of apicomplexan parasites is based upon the formation of daughter cytoskeletal scaffolds within the mother cell, which provide the framework for organellar replication and partition and are essential for parasite survival, therefore are attractive potential drug targets (Fig. 1).  In addition, the cytoskeletal scaffolds of these parasites are spectacular structures (Fig. 2), the biogenesis of which poses questions that are of general interest for cell biology (Fig. 3). 

The apicomplexan cytoskeletons are highly polarized and the body plan for assembly increasingly seems to be based on compartmentation along the apical-basal axis. The long term goal of our lab is to understand the origination, compartmentation and maturation of cytoskeletal scaffolds in the apicomplexan parasites using advanced light and electron microscopy, molecular biology, and proteomics techniques.  Our study will mainly focus on the cytoskeletal biogenesis of Toxoplasma gondii, because of its greater suitability for biochemical, light and electron microscopy investigation. In particular, we seek to answer the following questions:

    1. What are the very early processes that template the final structure of the Apicomplexan cytoskeletal scaffold, determine its striking polarity, and might provide clinically relevant targets for disruption of parasite replication? 
    2. When and where do these early steps occur?   
    3. What is the underlying molecular machinery that defines the structure and regulates the construction process? 

Answers to these questions will have important implications for general understanding of how specialized regions can be demarcated and assembled in highly polarized cells, for the biogenesis of the cytoskeleton of this group of important human pathogens, and consequently for the rational selection of chemotherapeutic targets for improved control of the Apicomplexan diseases.

Representative Publications:

Hu, K., Ji L., Applegate, K.T., Danuser G., Waterman-Storer C. 2007. "Differential Transmission of Actin Motion Within Focal Adhesions." Science 315:111-115.

K. Hu, J. Johnson, L. Florens, M. Fraunholz, S. Suravajjala, C. DiLullo, J. Yates, D. S. Roos and J. M. Murray   2006.”Cytoskeletal components of an invasion machine – the apical complex of Toxoplasma gondii” (cover) PloS Pathogens, 2(2): 0121-0138

K. Hu, D. S. Roos, S. O. Angel and J. M. Murray  2004. “Variability and heritability of cell division pathways in T. gondii” Journal of Cell Science  2004 117: 5697-5705

D. M. Wetzel, S. Hakansson, K. Hu, D. Roos, and L. D. Sibley  2003.  “Actin Filament Polymerization Propels Gliding Motility by Apicomplexan Parasites” Molec. Biol. Cell  14: 396-406

Pelletier, L., Stern, A., Pypaert, M., Sheff, D., Ngo, H., Roper, N., He, C., Hu, K., Toomre, D., Coppens, I., Roos, D., Joiner, K and Warren, G 2002. "Golgi Biogenesis in Toxoplasma gondii."  Nature  418, 548-552.

Swedlow, J.R., K. Hu, P.D. Andrews, D. S. Roos and J. M. Murray.  2002. “Measurement of tubulin content in the conoid and spindle pole of the parasite Toxoplasma gondii: A comparison of laser scanning confocal and wide field fluorescence microscopy for quantitative analysis in living cells” Proc. Nat'l Acad. Sci. USA 99:2014-2019.

Hu, K., D. S. Roos and J. M. Murray.  2002b.  “A novel polymer of tubulin forms the conoid in Toxoplasma gondii”(cover)  J. Cell Biol. 156:1039-1050.

Hu, K., T. Mann, B. Striepen, C.J. M. Beckers, D. S. Roos and J. M. Murray. 2002a. “Daughter cell assembly in the protozoan parasite Toxoplasma gondii”  Molec. Biol. Cell 13: 593-606.