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Vol. 19, Issue 1, 95-104, January 2008

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The Mitogen-activated Protein Kinase p38 Links Shiga Toxin-dependent Signaling and Trafficking

Sébastien Wälchli^*,, Sigrid S. Skånland^*,,,, Tone F. Gregers^*,, Silje U. Lauvrak^*,, Maria L. Torgersen^*,, Ming Ying^*, Shun'ichi Kuroda^||, Andrés Maturana^||,¶, and Kirsten Sandvig^*,,

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

Submitted June 14, 2007; Revised October 5, 2007; Accepted October 15, 2007
Monitoring Editor: Jennifer Lippincott-Schwartz

Shiga toxin (Stx) binds to the cell, and it 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 up-regulates 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 mitogen-activated protein kinase p38. Treatment of cells with chemical inhibitors or small interfering RNA targeting p38 inhibited Stx transport to the Golgi and reduced Stx toxicity. This p38 dependence is specific to Stx, because 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.

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.

Address correspondence to: Kirsten Sandvig (ksandvig{at}radium.uio.no)

Abbreviations used: Stx, Shiga toxin.