## 1 Introduction  
A number of protein toxins from plants or secreted by bacteria efficiently intoxate cells by binding to the cell surface and, after entry into the cytosol they inhibit the protein synthesis enzymatically, thereby killing the cell. Several of these toxins consist of two moieties, one that binds to cells and another that has enzymatic activity (for review, see [1]). Examples of two such toxins, the plant toxin ricin, which is found in the seeds of _Ricinus communis_, and the bacterial toxin Shiga toxin, which is secreted by _Shigella dysenteriae_, are shown in Figure 1. The enzymatically active moiety can, in both cases, inactivate the 60S subunit of the ribosome by removal of one adenine from the 28S RNA [2, 3]. Interestingly, several other plant toxins have a similar two-chain structure connected by a disulfide bridge. Although these toxins come from different plants, they share the ability to inactivate ribosomes in a similar manner. Such toxins are abrin, modeccin, viscumin, and volkensin [1]. About 40 years ago, researchers started to obtain information about how these toxins were able to become translocated to the cytosol. Data obtained at that time showed that some toxins appeared to enter the cytosol after endocytic uptake. For diphtheria toxin, another bacterial toxin able to inhibit protein synthesis (although by ADP-ribosylation of elongation factor 2) [7], there was some evidence for transfer into the cytosol after uptake since ammonium chloride, known to increase lysosomal pH, protected cells against intoxication [8]. In 1980, it was published that diphtheria toxin could enter directly through the cell membrane when cells with surface-bound nicked diphtheria toxin were exposed to low pH [9; 10]. This finding paved the road for similar investigations of several other toxins that also undergo a low pH-induced conformational change and subsequent translocation through the membrane [1]. What about other toxins that do not require low endosomal pH for entry into the cytosol? Is endocytosis irrelevant for the cytosolic entry? The structure of cholera toxin with a ring of B-subunits and the A-moiety in the middle led scientists to suggest that the A-moiety could somehow sink through the membrane and enter the cytosol. However, as we know today, this is not the case. In 1982, it was shown that ricin endocytosis under protective conditions, such as Ca\({}^{2+}\) deprivation or pH 6.0, intoxated cells when the protection was released [11]. This demonstrated that endocytosed toxin was able to enter the cytosol, and later studies revealed that several toxins, including Shiga toxin and ricin, are transferred to the Golgi and the ER before translocation to the cytosol (Figure 2). Actually, Shiga toxin was the first toxin found to be transported all the way from the cell surface to the Golgi and the ER [12]. The ability of these protein toxins to be translocated from the cell surface and retrogradely to the ER from where the A moieties are released have made them excellent tools to study the processes and transport steps involved. Their final effect on protein synthesis provides us with a very sensitive test system for the arrival in the cytosol. Thus, searching for compounds that protect against protein toxins not only can be of benefit in connection with disease or intoxication by these toxins but can help us to clarify transport pathways in the cells. The construction of genetically modified toxin molecules with sulfation sites, which are modified in the trans-Golgi, and glycosylation sites that can be modified in the ER [13; 14] has been of great help in revealing which step is affected. Thus, toxins have contributed to our knowledge about transport from the cell surface to endosomes, to the Golgi apparatus, and to the ER and nuclear envelope. The toxins can also be exploited to investigate how cells are  
Figure 1: The structure of (**A**) Shiga toxin (PDB ID:1 DM0 [4] and (**B**) ricin (PDB ID: 2 AAI) [5] determined by X-ray crystallography.