Pathways followed by ricin and Shiga toxin into cells

Abstract

The plant toxin ricin and the bacterial toxin Shiga toxin belong to a group of protein toxins that inhibit protein synthesis in cells enzymatically after entry into the cytosol. Ricin and Shiga toxin, which both have an enzymatically active moiety that inactivates ribosomes and a moiety that binds to cell surface receptors, enter the cytosol after binding to the cell surface, endocytosis by different mechanisms, and retrograde transport to the Golgi apparatus and the endoplasmic reticulum (ER). The toxins can be used to investigate the various transport steps involved, both the endocytic mechanisms as well as pathways for retrograde transport to the ER. Recent studies show that not only do several endocytic mechanisms exist in the same cell, but they are not equally sensitive to removal of cholesterol. New data have revealed that there is also more than one pathway leading from endosomes to the Golgi apparatus and retrogradely from the Golgi to the ER. Trafficking of protein toxins along these pathways will be discussed in the present article.

Cisplatin-induced expression of Gb3 enables verotoxin-1 treatment of cisplatin resistance in malignant pleural mesothelioma cells

“…The B part consists of five identical sub-units, which can all bind to the Gb3 receptor in which the A sub-unit is internalised and cytotoxic through ribosome inactivation (Endo et al, 1988;Olsnes and Sandvig, 1988;Saxena et al, 1989;O'Brien et al, 1992;Gariepy, 2001;Sandvig et al, 2002). VT-1 has shown efficacy against meningioma, astrocytoma, as well as renal tumour xenografts in mice (Arab et al, 1999;Salhia et al, 2002;Ishitoya et al, 2004).…”

The Intracellular Journey of Shiga Toxins

“…It is postulated that these toxins exploit an endogenous pathway for recycling of raft glycolipids and that the lipids mediate toxin transport all the way from the plasma membrane to the ER [87,89]. In agreement with this, disruption of lipid rafts or reduction of cellular cholesterol by drugs such as m CD or filipin, was found to strongly reduce transport of Stx to the Golgi [55,87]. However, not only lipid raft integrity, but also specific targeting of the Stx/Gb3 complex to these domains seems to be important for retrograde transport [87].…”

“…Stx has been shown to utilize the direct pathway to the TGN, and not the Rab9-dependent pathway via late endosomes that transports amongst others, furin and a fraction of Pseudomonas exotoxin A [48,[52][53][54][55]. However, based on the differential requirements for retrograde transport of Stx, ricin and TGN38, it seems that more than one parallel pathway between early endosomes and the TGN may exist [32,33,[56][57][58][59][60][61][62].…”

“…Rab11 [60], Rab6a [59,63], and Rab6IP2 [64] have all been reported to positively regulate Stx transport, while Rab9 does not seem to be required for transport of either ricin or Stx [55,56]. In a screen for potential Rab GTPase activating proteins (RabGAPs) involved in transport of Stx to the Golgi, the Golgi-localized Rab43 and its RabGAP RN-tre were found to be required [65].…”

The emergence of multiple particle tracking in intracellular trafficking of nanomedicines

“…While their later stages are not clearly identified, they appear to bypass the rab5-positive early endosomes. Ricin and Shiga toxins utilize clathrin-and caveolae-independent mechanisms for transport to the Golgi apparatus and, subsequently, to the ER (Sandvig et al 2002). There are not many nanoparticle systems known to utilize clathrin-and caveolae-independent endocytosis.…”