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Published online September 24, 2007
doi:10.1083/jcb.200705021
The Journal of Cell Biology, Vol. 178, No. 7, 1265-1278
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Alto et al.
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Article

 The type III effector EspF coordinates membrane trafficking by the spatiotemporal activation of two eukaryotic signaling pathways

Neal M. Alto1, Andrew W. Weflen3, Matthew J. Rardin1, Defne Yarar4, Cheri S. Lazar1, Raffi Tonikian5, Antonius Koller2, Susan S. Taylor2, Charles Boone5, Sachdev S. Sidhu6, Sandra L. Schmid4, Gail A. Hecht3, and Jack E. Dixon1,2

1 Departments of Pharmacology, Cellular and Molecular Medicine, and Chemistry and Biochemistry and 2 The Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093
3 Department of Medicine, Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL 60612
4 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
5 Banting and Best Department of Medical Research and Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 3E1, Canada
6 Department of Protein Engineering, Genentech Inc., South San Francisco, CA 94080

Correspondence to Jack E. Dixon: jedixon{at}ucsd.edu

Bacterial toxins and effector proteins hijack eukaryotic enzymes that are spatially localized and display rapid signaling kinetics. However, the molecular mechanisms by which virulence factors engage highly dynamic substrates in the host cell environment are poorly understood. Here, we demonstrate that the enteropathogenic Escherichia coli (EPEC) type III effector protein EspF nucleates a multiprotein signaling complex composed of eukaryotic sorting nexin 9 (SNX9) and neuronal Wiskott-Aldrich syndrome protein (N-WASP). We demonstrate that a specific and high affinity association between EspF and SNX9 induces membrane remodeling in host cells. These membrane-remodeling events are directly coupled to N-WASP/Arp2/3–mediated actin nucleation. In addition to providing a biochemical mechanism of EspF function, we find that EspF dynamically localizes to membrane-trafficking organelles in a spatiotemporal pattern that correlates with SNX9 and N-WASP activity in living cells. Thus, our findings suggest that the EspF-dependent assembly of SNX9 and N-WASP represents a novel form of signaling mimicry used to promote EPEC pathogenesis and gastrointestinal disease.

A.W. Weflen, M.J. Rardin, and D. Yarar contributed equally to this paper.

N.M. Alto's present address is Department of Microbiology, University of Texas Southwestern Medical Center, S323 Harry Hines Blvd., Dallas, TX 75390-9048.

Abbreviations used in this paper: A/E, attaching and effacing; BAR, Bin/Amphiphysin/Rvs; CCP, clathrin-coated pit; CRIB, Cdc42/rac interactive binding; EHEC, enterohaemorrhagic Escherichia coli; EPEC, enteropathogenic Escherichia coli; N-WASP, neuronal Wiskott-Aldrich syndrome protein; PRR, proline-rich repeat; PX, phox; SH3, Src homology-3; SNX9, sorting nexin 9; TER, trans-epithelial electrical resistance; TTSS, type III secretion system.


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