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| Subject Categories: Cell & Tissue Architecture | Molecular Biology of Disease |
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| The EMBO Journal
(2007) 26, 2240–2250, doi:10.1038/sj.emboj.7601687 Published online 19 April 2007 |
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| Anthrax lethal toxin paralyzes actin-based motility by blocking Hsp27 phosphorylation |
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| Russell L During1, 2, Bruce G Gibson1, 2, Wei Li1, 2, Ellen A Bishai1, 2, Gurjit S Sidhu1, 2, Jacques Landry3 and Frederick S Southwick1, 2, 4 |
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1 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA 2 Department of Infectious Diseases, University of Florida College of Medicine, Gainesville, FL, USA 3 Centre de recherche en cancérologie de l'Université Laval, CHUQ-HDQ, Québec, Canada 4 None of the authors have commercial or other associations that might pose a conflict of interest To whom correspondence should be addressed Frederick S Southwick, Division of Infectious Diseases, University of Florida College of Medicine, Box 100277, 1600 Archer Rd., Gainesville, FL 32610, USA. Tel.: +1 352 392 4058; Fax: +1 352 392 6481; E-mail: southfs@medicine.ufl.edu Received 4 October 2006; Accepted 22 March 2007; Published online 19 April 2007. |
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| Abstract |
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| Inhalation of anthrax causes fatal bacteremia, indicating a meager host immune response. We previously showed that anthrax lethal toxin (LT) paralyzes neutrophils, a major component of innate immunity. Here, we have found that LT also inhibits actin-based motility of the intracellular pathogen Listeria monocytogenes. LT inhibition of actin assembly is mediated by blockade of Hsp27 phosphorylation, and can be reproduced by treating cells with the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580. Nonphosphorylated Hsp27 inhibits Listeria actin-based motility in cell extracts, and binds to and sequesters purified actin monomers. Phosphorylation of Hsp27 reverses these effects. RNA interference knockdown of Hsp27 blocks LT inhibition of Listeria actin-based motility. Rescue with wild-type Hsp27 accelerates Listeria speed in knockdown cells, whereas introduction of Hsp27 mutants incapable of phosphorylation or dephosphorylation causes slowing down. We propose that Hsp27 facilitates actin-based motility through a phosphorylation cycle that shuttles actin monomers to regions of new actin filament assembly. Our findings provide a previously unappreciated mechanism for LT virulence, and emphasize a central role for p38 MAP kinase-mediated phosphorylation of Hsp27 in actin-based motility and innate immunity. |
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| Keywords: actin-regulatory proteins, anthrax, heat-shock proteins, lethal toxin, p38 MAP kinase |
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