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Chapter 11 : Transport of Toxins across Intracellular Membranes

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Transport of Toxins across Intracellular Membranes, Page 1 of 2

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Abstract:

A number of protein toxins with a cytosolic target act on cells by first binding to cell surface receptors, then the toxins are endocytosed, and subsequently they are transported to the organelle from where they are translocated to the cytosol. In spite of the structural similarities between these toxins, they use different strategies to enter the cytosol. Most protein toxins have to be endocytosed before being translocated to the cytosol. Only few exceptions are known; one is the adenylate cyclase from , which enters the cytosol directly through the plasma membrane. A number of protein toxins enter the cytosol either from acidic endosomes or from the endoplasmic reticulum (ER) after retrograde transport from endosomes to the Golgi apparatus and to the ER. Endocytosis of protein toxins can occur by several mechanisms. Cholera toxin was the first bacterial toxin visualized in the Golgi apparatus. Later, toxin transport to the Golgi apparatus has been demonstrated for several other protein toxins as well. Both bacterial toxins and plant toxins such as ricin are transported from endosomes to the Golgi apparatus. There is a lively transport of newly synthesized proteins from the cytosol and into the ER lumen through the Sec61p complex. It is also known that this protein complex is used for transport of misfolded protein in the other direction, back into the cytosol, where these proteins can be ubiquitinylated, deglycosylated, and degraded by proteasomes.

Citation: Sandvig K. 2003. Transport of Toxins across Intracellular Membranes, p 157-172. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch11

Key Concept Ranking

Golgi Apparatus
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A-B Toxins
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Figures

Image of Figure 1
Figure 1

Schematic structure and effects of A-B toxins. The enzymatically active part (A) and the binding moiety (B) can either be covalently or noncovalently attached to each other. In some toxins the binding moiety consists of several subunits. In several cases there is a disulfide bond that keeps the toxin moieties together after a proteolytic cleavage, which can occur before (white arrow) or after (black arrow) the toxin is presented to the target cell. When the toxins are cleaved by the target cells, it is usually the enzyme furin that is responsible for the activation. In the case of anthrax toxin, the furininduced cleavage of the B moiety at the cell surface allows subsequent binding of the A moiety. The enzymatic effects and cellular targets are indicated.

Citation: Sandvig K. 2003. Transport of Toxins across Intracellular Membranes, p 157-172. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch11
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Image of Figure 2
Figure 2

Translocation of the enzymatically active moiety of A-B toxins to the cytosol occurs from different intracellular organelles. After endocytosis some toxins like diphtheria toxin (DT) (see details in Fig. 4 ), anthrax toxin, CNF1, C2 toxin, and clostridial neurotoxins are transported from endosomes by a low pH-induced translocation process that may require the toxin receptor and in some cases requires the proteolytically cleaved toxin. In this figure no distinction has been made between early and late endosomes. Toxin entry may occur from one or the other, and this seems to be dependent on the type of toxin. Other toxins are transported to the Golgi apparatus and retrogradely to the ER before translocation of the A moiety to the cytosol. This group of toxins include the bacterial toxins exotoxin A, cholera toxin, Shiga toxin, and pertussis toxin as well as the plant toxin ricin. Only entry of the enzymatically active part is indicated in the figure. However, a larger part of the toxin molecule might enter the cytosol.

Citation: Sandvig K. 2003. Transport of Toxins across Intracellular Membranes, p 157-172. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch11
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Image of Figure 3
Figure 3

Endocytic mechanisms proposed to be involved in toxin uptake. Clathrin-dependent endocytosis has previously been blocked by hypotonic shock and potassium depletion or by acidification of the cytosol. In more recent studies this pathway was inhibited by expression of a dominant negative mutant of dynamin 1 (dynamin K44A), by Eps15 mutants, and by expression of antisense to clathrin heavy chain. Formation of invaginated clathrin-dependent structures seems to be dependent on cholesterol since treatment of cells with methyl--cyclodextrin (mCD) inhibits their formation. Only flat coated pits are seen after such treatment. Clathrin-independent endocytosis comprises more than one mechanism and can be independent from a possible uptake from caveolae. There are both dynamin-dependent and -independent forms of the clathrin- and caveolaeindependent endocytosis, and uptake of a ligand by such a mechanism can in some cases be dependent on membrane cholesterol whereas in other cases it is not. Uptake by caveolae has been reported to be dependent on dynamin and can be inhibited by extraction of cholesterol or complex formation of cholesterol with filipin or nystatin. Interfering with the different endocytic pathways has revealed that diphtheria toxin (DT), exotoxin A, Shiga toxin, and also to some extent cholera toxin are internalized by clathrindependent endocytosis. Both CNF1 and to some extent cholera toxin are internalized independently of caveolae.

Citation: Sandvig K. 2003. Transport of Toxins across Intracellular Membranes, p 157-172. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch11
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Image of Figure 4
Figure 4

Membrane translocation of diphtheria toxin. Proposed mechanism of low pH-induced diphtheria toxin entry across the membrane. Low endosomal pH will induce a conformational change in the molecule as well as protonation of Asp-352 and Glu-349 in the B chain, insertion of the toxin into the membrane, and translocation and release of the A chain. Insertion of the B chain into the membrane is associated with formation of cation-selective channels.

Citation: Sandvig K. 2003. Transport of Toxins across Intracellular Membranes, p 157-172. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch11
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Image of Figure 5
Figure 5

Endosome to Golgi transport. Endocytosed furin and M6PRs are transported to the Golgi apparatus through late endosomes by a Rab9-dependent pathway, whereas Shiga toxin, the plant toxin ricin, and the cellular protein TGN38 can enter the Golgi apparatus from an earlier endosomal compartment. In the case of ricin, transport to the Golgi apparatus occurs by a Rab9- and clathrin-independent process.

Citation: Sandvig K. 2003. Transport of Toxins across Intracellular Membranes, p 157-172. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch11
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Image of Figure 6
Figure 6

Retrograde transport through the Golgi apparatus. Toxins with a KDEL sequence or a KDEL-like sequence might be transported retrogradely by a COPI-dependent mechanism, whereas other toxins, such as Shiga toxin, can enter the ER by a COPI-independent, Rab6-dependent pathway. It is not clear whether this pathway goes via the different cisternae of the Golgi apparatus or whether Shiga toxin observed in the different cisternae ends up in these locations via a different mechanism.

Citation: Sandvig K. 2003. Transport of Toxins across Intracellular Membranes, p 157-172. In Burns D, Barbieri J, Iglewski B, Rappuoli R (ed), Bacterial Protein Toxins. ASM Press, Washington, DC. doi: 10.1128/9781555817893.ch11
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