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Cell Motility, Membrane Ruffling and Cell Death

Shaun Lee

Appointment Period: 2004-2006 / Grant Years: [20,21]

Shaun LeeThe regulation of the host cell cytoskeleton is an important determinant of oncogenesis. The ability of a cancer to migrate is governed by the regulators of cytoskeletal dynamics, in particular the Rho family of GTPases. Furthermore, RhoGTPases govern cancer cell motility, and control the levels and timing of expression of cell-cycle regulators. Investigating the means by which bacteria alter the host cell cytoskeleton may provide additional clues into how these pathways influence oncogenesis, and may allow the development of novel therapeutics.

A common strategy among bacterial pathogens is the alteration of host cell signaling processes for virulence. Many virulence factors target pathways involved in cell growth, regulation, and cell motility. Studying the mechanisms by which bacteria alter these processes may provide additional insights into the cellular regulation of these pathways. Enteropathogenic and enterohaemorrhagic E. coli (EPEC, EHEC) are closely related diarrheagenic human pathogens. EPEC and EHEC contain a type III secretion system (TTSS) that translocates effector proteins into infected cells to modify host cell processes and influence pathogenesis. My project is to characterize the mechanism by which EspH, a known effector protein modulates the host cytoskeleton to influence infectivity. Overexpression of EspH in HEK 293a human cells resulted in disruption of the cytoskeleton and produced a cell rounding phenotype, consistent with earlier published reports. When we expressed constitutively active forms of Rho, Rac, and Cdc42 with EspH and examined the cells by immunofluorescence microscopy, only Rac was observed to rescue the cell rounding phenotype induced by EspH. We are currently investigating the role of the RacGTPase pathway in EspH-induced host cell cytoskeletal modification, along with coimmunoprecipitation and yeast-two-hybrid approaches to identify cellular targets of EspH.

Yooseph S, Sutton G, Rusch DB, Halpern AL, Williamson SJ, Remington K, Eisen JA, Heidelberg KB, Manning G, Li W, Jaroszewski L, Cieplak P, Miller CS, Li H, Mashiyama ST, Joachimiak MP, van Belle C, Chandonia JM, Soergel DA, Zhai Y, Natarajan K, Lee S, Raphael BJ, Bafna V, Friedman R, Brenner SE, Godzik A, Eisenberg D, Dixon JE, Taylor SS, Strausberg RL, Frazier M, Venter JC. The Sorcerer II Global Ocean Sampling expedition: expanding the universe of protein families. PLoS Biol. (2007) 5:e16. PMID: 17355171; PMCID: PMC1821046.

Lee SW, Mitchell DA, Markley AL, Hensler ME, Gonzalez D, Wohlrab A, Dorrestein PC, Nizet V, Dixon JE. Discovery of a widely distributed toxin biosynthetic gene cluster. Proc Natl Acad Sci USA. (2008) 105:5879-84. PMID: 18375757; PMCID: PMC2311365.

Mitchell DA, Lee SW, Pence MA, Markley AL, Limm JD, Nizet V, Dixon JE. Structural and functional dissection of the heterocyclic peptide cytotoxin streptolysin S. J Biol Chem. (2009) 284:13004-12. PMID: 19286651; PMCID: PMC2676033.

Gonzalez DJ, Lee SW, Hensler ME, Markley AL, Dahesh S, Mitchell DA, BandeiraN, Nizet V, Dixon JE, Dorrestein PC. Clostridiolysin S, a post-translationallymodified biotoxin from Clostridium botulinum. J Biol Chem. 2010 Sep3;285(36):28220-8. Epub 2010 Jun 25. PubMed PMID: 20581111; PubMed Central PMCID:PMC2934687.