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J. Biol. Chem., Vol. 282, Issue 22, 16317-16328, June 1, 2007

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Protein Kinase C Is Activated by Shiga Toxin and Regulates Its Transport^*

Maria L. Torgersen, Sébastien Wälchli, Stine Grimmer, Sigrid S. Skånland, and Kirsten Sandvig¹

From the Institute for Cancer Research, Faculty Division, The Norwegian Radium Hospital, University of Oslo, Montebello, 0310 Oslo and the Department of Molecular Biosciences, University of Oslo, 0316 Oslo, Norway

Protein kinase C (PKC) isozymes regulate different vesicular trafficking steps in the recycling or degradative pathways. However, a possible role of these kinases in the retrograde pathway from endosomes to the Golgi complex has previously not been investigated. We report here the involvement of a specific PKC isozyme, PKC, in the intracellular transport of the glycolipid-binding Shiga toxin (Stx), which utilizes the retrograde pathway to intoxicate cells. Upon binding to cells, Stx was shown to specifically activate PKC and not PKC. The involvement of PKC and PKC in the retrograde transport of Stx was then monitored biochemically and by immunofluorescence after inhibition or depletion of the isozymes. PKC, but not PKC, was shown to selectively regulate the endosome-to-Golgi transport of StxB. Upon inhibition or knockdown of PKC, StxB molecules colocalized less with giantin and more with EEA1, indicating that the molecules were accumulated in endosomes, unable to reach the Golgi complex. The inhibition of Golgi transport of Stx was reflected by a strong reduction in the toxic effect, demonstrating that transport of Stx to the cytosol is dependent on PKC activity. These results are in agreement with our previous data, which show that Stx is able to stimulate its own transport.

Received for publication, November 27, 2006 , and in revised form, March 14, 2007.

^* This work was supported by the Norwegian Cancer Society, the Norwegian Research Council for Science and the Humanities, the National Program for Research in Functional Genomics in Norway in The Research Council of Norway, the Novo-Nordisk Foundation, the Jahre Foundation, and the Jeanette and Søren Bothners Legacy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Tel.: 47-229-34294; Fax: 47-225-08692; E-mail: ksandvig{at}radium.uio.no.

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