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MBC in Press, published online ahead of print October 24, 2007
Mol. Biol. Cell 10.1091/mbc.E07-06-0565

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Submitted on June 14, 2007
Revised on October 5, 2007
Accepted on October 15, 2007

The MAP Kinase p38 Links Shiga Toxin Dependent Signaling and Trafficking

Sébastien Wälchli,*{dagger} Sigrid S. Skånland,*{dagger}{ddagger}{sect} Tone F. Gregers,*{sect} Silje U. Lauvrak,*{ddagger} Maria L. Torgersen,*{ddagger} Ming Ying,* Shun’ichi Kuroda,|| Andrés Maturana,||¶ and Kirsten Sandvig*{ddagger}{sect}

*Department of Biochemistry and {ddagger}Centre for Cancer Biomedicine, Institute for Cancer Research, The Norwegian Radium Hospital, University of Oslo, Montebello, N-0310 Oslo, Norway; {sect}Department of Molecular Biosciences, University of Oslo, N-0316 Oslo, Norway; ||Department of Structural Molecular Biology, ISIR SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki Osaka 567-0047, Japan

Monitoring Editor: Jennifer Lippincott-Schwartz

Shiga toxin (Stx) binds to the cell and is transported via endosomes and the Golgi apparatus to the endoplasmic reticulum and cytosol, where it exerts its toxic effect. We have recently shown that Stx activates the tyrosine kinase Syk, which in turn induces clathrin phosphorylation and upregulates Stx uptake. Here, we show that toxin-induced signaling can also regulate another step in intracellular Stx transport. We demonstrate that transport of Stx to the Golgi apparatus is dependent on the MAP kinase p38. Treatment of cells with chemical inhibitors or siRNA targeting p38, inhibited Stx transport to the Golgi and reduced Stx toxicity. This p38 dependency is specific to Stx since transport of the related toxin ricin was not affected by p38 inhibition. Stx rapidly activated p38, and recruited it to early endosomes in a Ca2+-dependent manner. Furthermore, agonist-induced oscillations in cytosolic Ca2+ levels were inhibited upon Stx stimulation, possibly reflecting Stx-dependent local alterations in cytosolic Ca2+ levels. Intracellular transport of Stx is Ca2+-dependent, and we provide evidence that Stx activates a signaling cascade involving cross-talk between Ca2+ and p38, to regulate its trafficking to the Golgi apparatus.

Address correspondence to:

{dagger}These authors contributed equally to this work.

Present address: Global Edge Institute, Tokyo Institute of Technology, 4259-B4 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan. Kirsten Sandvig (ksandvig{at}radium.uio.no)




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