Retrograde transport of endocytosed Shiga toxin to the endoplasmic reticulum

SHIGA toxin and some other protein toxins that act on targets in the cytosol have previously been shown to enter the trans-Golgi network1-9. Transport by this route may be necessary for translocation of the toxin to the cytosol and for intoxication5-9, but it is not known whether the enzymatically active part of the toxins actually enters the cytosol from the trans-Golgi network. It has been suggested that such toxins are transported in a retrograde manner to the endoplasmic reticulum and that translocation occurs in this organelle10, but retrograde transport of endocytosed material beyond the trans-Golgi network has never been demonstrated. Here we show that in butyric acid-treated A431 cells endocytosed Shiga toxin is not only transported to the trans-Golgi network, but also to all Golgi stacks, to the endoplasmic reticulum and to the nuclear envelope. Furthermore, butyric acid sensitizes the cells to Shiga toxin, which is consistent with the possibility that retrograde transport is required for translocation of the toxin to the cytosol.