Endocytosis and retrograde transport of Shiga toxin

doi:10.1016/j.toxicon.2009.11.021

Toxicon

Volume 56, Issue 7, 15 December 2010, Pages 1181-1185

https://doi.org/10.1016/j.toxicon.2009.11.021 Get rights and content

Abstract

Shiga toxin belongs to the group of bacterial and plant toxins that act on cells by binding to cell surface receptors via a binding-moiety, then the toxins are endocytosed and transported retrogradely to the Golgi apparatus and the endoplasmic reticulum (ER) before an enzymatically active moiety enters the cytosol and exerts the toxic effect. In the case of Shiga toxin, similarly to plant toxins such as ricin and viscumin, the toxin removes one adenine from the 28S RNA of the 60S subunit of the ribosome and thereby inhibits protein synthesis. This ribotoxic effect is in some cells followed by apoptosis. In this article we focus on new discoveries concerning endocytosis and retrograde transport of Shiga toxin to the Golgi, the ER and the cytosol.

Introduction

Shiga toxin, secreted by Shigella dysenteria, and Shiga-like toxins (Stx1 and Stx2) secreted by E. coli and other bacteria, are still a problem in infectious diseases (Karmali, 2004, Palermo et al., 2009, Sandvig, 2006). During recent years there seems to be an increasing problem with food contaminated with E. coli producing these toxins, which may cause kidney failure, especially in children (Palermo et al., 2009). However, Shiga toxin can also be exploited for medical purposes. The receptor for the toxin, globotriaosylceramide (Gb3), is to a certain extent specifically associated with malignant, even metastasizing cells, and this can be exploited for diagnosis and treatment of cancer (Distler et al., 2009, El Alaoui et al., 2007, Johannes and Decaudin, 2005, Kovbasnjuk et al., 2005). Furthermore, studies of entry of Shiga toxin into cells have proven useful to explore intracellular pathways and their regulation (Johannes and Popoff, 2008, Sandvig et al., 1992, Torgersen et al., in press).

Section snippets

Structure of Shiga toxin and its interaction with the receptor molecule Gb3

Shiga toxin is, as shown in Fig. 1, composed of one A-moiety, consisting of the domains A1 and A2 which is non-covalently associated with the pentamer of B-subunits, each able to bind three Gb3 molecules. In order for the A-moiety to exert enzymatic activity, the A1 needs to be released into the cytosol. As in several other bacterial protein toxins (Gordon and Leppla, 1994), there is a furin cleavage-site in the toxin. In the case of Shiga toxin the furin recognition sequence RXXR is found

Endocytosis of Shiga toxin

After binding of Shiga toxin to the receptor, Gb3, the toxin is endocytosed by different endocytic pathways (Falguieres et al., 2001, Sandvig et al., 2008). Interestingly, the ability of the toxin to activate the kinase Syk is important for its uptake by clathrin-dependent endocytosis (Lauvrak et al., 2006), and the toxin induces formation of a complex containing Syk and clathrin, and leads to clathrin heavy-chain phosphorylation (Lauvrak et al., 2002, Walchli et al., 2009). The importance of

Sorting of Shiga toxin from endosomes to the Golgi apparatus

An important step for intoxication with Shiga toxin is sorting from endosomes to the Golgi apparatus. There are cells which bind and endocytose the toxin, but which are completely resistant to the toxin and where no Golgi transport is observed (Falguieres et al., 2001, Sandvig et al., 1992). In fact, the first demonstration of retrograde toxin transport to the Golgi and the ER was performed in A431 cells, which are normally completely resistant to the toxin, but can be made very sensitive by

Retrograde transport through the Golgi and to the ER/cytosol

Investigations of retrograde transport in different laboratories have revealed that there seems to be more than one mechanism involved in transport between the Golgi apparatus and the ER. Both COPI-dependent and -independent transport routes have been demonstrated, and studies have shown that Shiga toxin can be transported by a COPI-independent, but Rab6a′ and Cdc42-dependent transport route that is dependent on Yip1A, microtubules and actin (del Nery et al., 2006, Duran et al., 2003, Johannes

Conclusions

Investigations of Shiga toxin entry into cells is warranted due to the serious infectious diseases caused by bacteria that secrete Shiga toxin and Shiga-like toxins. Moreover, studies of Shiga toxin transport have also proven useful to discover and characterize basic processes in cell biology, such as endocytosis of lipid-bound ligands and retrograde transport to the Golgi apparatus and the ER. Important is also the use of Shiga toxin in medicine, for instance, both when it comes to cancer

Acknowledgement

This work has been supported by the Norwegian Cancer Society, the Norwegian Research Council for Science and the Humanities, and Helse Sør-Øst, Norway.

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ReviewEndocytosis and retrograde transport of Shiga toxin

Abstract

Introduction

Section snippets

Structure of Shiga toxin and its interaction with the receptor molecule Gb3

Endocytosis of Shiga toxin

Sorting of Shiga toxin from endosomes to the Golgi apparatus

Retrograde transport through the Golgi and to the ER/cytosol

Conclusions

Acknowledgement

Biophys. Res. Commun.

Exp. Cell Res.

J. Biol. Chem.

Cell

Biochem. Biophys. Res. Commun

Dev. Cell

J. Biol. Chem.

Biochem. Biophys. Res. Comm

Cell. Signal

The retromer component sorting nexin-1 is required for efficient retrograde transport of Shiga toxin from early endosome to the trans Golgi network

J. Cell Sci

Rab6A and Rab6A′ GTPases play non-overlapping roles in membrane trafficking

Traffic

Myosin motors and not actin comets are mediators of the actin-based Golgi-to-endoplasmic reticulum protein transport

Mol. Biol. Cell

Shiga toxin-mediated retrograde delivery of a topoisomerase I inhibitor prodrug

Angew. Chem. Int. Ed Engl

Targeting of Shiga toxin B-subunit to retrograde transport route in association with detergent-resistant membranes

Mol. Biol. Cell

Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool

Mol. Cancer Ther

Proteolytic activation of bacterial toxins: role of bacterial and host cell proteases

Infect. Immun

Endosome to Golgi transport of ricin is regulated by cholesterol

Mol. Biol. Cell

Depletion of sphingolipids facilitates endosome to Golgi transport of ricin

Traffic

SDPR induces membrane curvature and functions in the formation of caveolae

Nat. Cell Biol.

Shiga toxin facilitates its retrograde transport by modifying microtubule dynamics

Mol. Biol. Cell

Review
Endocytosis and retrograde transport of Shiga toxin