QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 20, 4303-4312, October 15, 2009

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E09-02-0155v1 20/20/4303    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Hehnly, H. Articles by Stamnes, M. PubMed PubMed Citation Articles by Hehnly, H. Articles by Stamnes, M.

Retrograde Shiga Toxin Trafficking Is Regulated by ARHGAP21 and Cdc42

Heidi Hehnly^*, Katrina Marie Longhini^*, Ji-Long Chen^,, and Mark Stamnes^*

*Department of Molecular Physiology and Biophysics, and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA 52242

Submitted February 25, 2009; Revised August 4, 2009; Accepted August 11, 2009
Monitoring Editor: Adam Linstedt

Shiga-toxin–producing Escherichia coli remain a food-borne health threat. Shiga toxin is endocytosed by intestinal epithelial cells and transported retrogradely through the secretory pathway. It is ultimately translocated to the cytosol where it inhibits protein translation. We found that Shiga toxin transport through the secretory pathway was dependent on the cytoskeleton. Recent studies reveal that Shiga toxin activates signaling pathways that affect microtubule reassembly and dynein-dependent motility. We propose that Shiga toxin alters cytoskeletal dynamics in a way that facilitates its transport through the secretory pathway. We have now found that Rho GTPases regulate the endocytosis and retrograde motility of Shiga toxin. The expression of RhoA mutants inhibited endocytosis of Shiga toxin. Constitutively active Cdc42 or knockdown of the Cdc42-specific GAP, ARHGAP21, inhibited the transport of Shiga toxin to the juxtanuclear Golgi apparatus. The ability of Shiga toxin to stimulate microtubule-based transferrin transport also required Cdc42 and ARHGAP21 function. Shiga toxin addition greatly decreases the levels of active Cdc42-GTP in an ARHGAP21-dependent manner. We conclude that ARHGAP21 and Cdc42-based signaling regulates the dynein-dependent retrograde transport of Shiga toxin to the Golgi apparatus.

Present address: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China.

Address correspondence to: Mark Stamnes (mark-stamnes{at}uiowa.edu).

Abbreviations used: ARF1, ADP-ribosylation factor; Gb3, globotriaosyl ceramide; MT, microtubule; STxB, Shiga toxin B subunit.