Traffic and Signaling Laboratory, Curie Institute, UMR144 Curie/ Centre National de la Recherche Scientifique, F-75248 Paris Cedex 05, France
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ABSTRACT |
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Many intracellular transport routes are still little explored. This is particularly true for retrograde transport between the plasma membrane and the endoplasmic reticulum. Shiga toxin B subunit has become a powerful tool to study this pathway, and recent advances on the molecular mechanisms of transport in the retrograde route and on its physiological function(s) are summarized. Furthermore, it is discussed how the study of retrograde transport of Shiga toxin B subunit allows one to design new methods for the intracellular delivery of therapeutic compounds.
Shigella dysenteriae; endocytosis; endosomes; Golgi apparatus; signaling; vaccination
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INTRODUCTION |
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SHIGA TOXIN IS A BACTERIAL protein toxin produced by Shigella dysenteriae. It is highly related to the family of verotoxins (or Shiga-like toxins) produced by enterohemorrhagic strains of Escherichia coli. Verotoxin 1 is essentially the same protein as Shiga toxin. Verotoxins, together with other bacterial products such as lipopolysaccharide and enterohemolysin, cause hemorrhagic colitis, which may progress to life-threatening complications such as hemolytic and uremic syndrome (for a review, see Ref. 24). However, their exact role in pathogenesis remains elusive. Verotoxins most likely contribute to endothelial and epithelial cell damage, acute pediatric kidney failure, hemolytic anemia, and thrombocytopenia.
Shiga toxin is a member of the group of toxins with AB5 subunit structure. Both subunits are noncovalently linked. The A subunit has a ribosomal RNA N-glycanase activity. The toxin-catalyzed modification of ribosomes leads to an inhibition of protein biosythesis in a subset of receptor-expressing cells, such as highly toxin-sensitive HeLa and Vero cells. Other cells, such as human monocytes and monocyte-derived cells, i.e., macrophages and dendritic cells (see Ref. 4 and references therein), express the receptor but are resistant to toxin-mediated inhibition of protein biosynthesis. This difference is likely related to differences in intracellular transport.
The B subunit of Shiga toxin binds to the cellular toxin receptor, the
glycosphingolipid globotriaosyl ceramide (Gb3 or CD77). The
structure of Shiga toxin B subunit has been determined by X-ray
crystallography and nuclear magnetic resonance studies. The protein's
pentamer is arranged around a central pore that is lined by
-helixes, giving the complex a doughnutlike appearance. Mutational,
modeling, biophysical, and crystallographic studies suggest the
existence of two or three binding sites for Gb3 per monomer, with site 3 appearing to be of minor importance in
vivo (see Ref. 29 and references therein). These data,
despite some inconsistencies that probably originate from the use of
different techniques, all agree with biophysical studies showing that
receptor binding by Shiga toxin is a cooperative phenomenon, likely
implicating binding of several lipids per pentamer. The binding of the
A subunit to the B subunit does not alter the structure of the latter,
and available evidence suggests that holotoxin and B subunit bind to
cells and are transported within cells at least qualitatively in the
same manner.
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SHIGA TOXIN B SUBUNIT AS A TOOL TO STUDY INTRACELLULAR TRANSPORT |
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In a pioneering work, Sandvig, van Deurs, and colleagues (see
references within Ref. 13) showed that Shiga toxin could
be detected in the endoplasmic reticulum (ER) of target cells that are
sensitive to toxin-mediated inhibition of protein biosynthesis (Fig.
1). Transport to the ER most likely
places the A subunit of the toxin in an environment that is compatible
with membrane translocation into the cytosol. Indeed, a process termed
retrotranslocation or ER-associated protein degradation allows some
luminal proteins to leave the ER, and for the plant protein toxin
ricin, conclusive evidence has been presented by Olsnes, Lord, and
colleagues in favor of a role of the retrotranslocation machinery in
toxin transport to the cytosol (for references, see Ref.
4).
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The discovery of Shiga toxin in the ER has stimulated a flurry of research around what is known today as the retrograde transport route, and the use of biochemical tools has allowed establishing its current model (Fig. 1; for a review, see Ref. 13). From the plasma membrane, the B subunit of Shiga toxin is internalized into the early endosome. It is then directly transported to the trans-Golgi network (TGN) and the Golgi apparatus, bypassing the late endocytic pathway. From the TGN/Golgi apparatus, the B subunit reaches the ER via a pathway that appears to be independent of classic recycling markers at the Golgi-ER interface, such as the Lys-Asp-Glu-Leu (KDEL) receptor and the coatomer protein I (COPI) coat (for a review, see Ref. 12).
The different transport steps in the retrograde route have been studied in further detail, and sometimes apparently contradictory evidence has been obtained. It should be kept in mind, however, that our understanding of this pathway is still very incomplete. In the following sections, the individual transport steps are briefly discussed, and special attention is paid to point out where studies diverge.
Endocytosis. In earlier work, it was described that Shiga toxin could be detected in clathrin-coated pits and vesicles, and pharmacological treatments that have effects on clathrin-mediated endocytosis inhibited Shiga toxin activity on cells (original work cited in Ref. 13). More recently, the use of molecular inhibitors of AP2 function, the clathrin adaptor complex at the plasma membrane, combined with video experiments has led to the proposal that Shiga toxin B subunit transport to the Golgi apparatus does not depend on the clathrin machinery at the plasma membrane (22). Different explanations can be proposed to reconcile these apparently contradictory data. Apart from trivial ones, such as heterogeneity linked to the different cell systems that were used in these studies, it might also be suggested that Shiga toxin can actually enter cells via both the clathrin-dependent and -independent routes. It is possible that, in both cases, the protein could still have access to the Golgi apparatus. Similar observations were made for sphingomyelin, which was found to enter cells via both endocytic pathways, and inhibition of neither one abolished targeting to the Golgi apparatus (25). The use of truly quantitative methods and of specific molecular inhibitors will allow sorting out of this question.
Endosome-to-Golgi transport. The description of a direct and efficient pathway between the early endosome and the Golgi apparatus (13) came as a surprise in that is was commonly admitted that the endocytic pathway is linked to the biosynthetic/secretory pathway at the level of late endosomes (Fig. 1). This direct early endosome-to-TGN connection was then put forward, being a leakage pathway allowing small fractions of molecules with exquisite activities, such as the protein toxins, to escape from late endosomal/lysosomal degradation. However, several arguments now suggest that early endosome-to-TGN transport is a preexisting, efficient, "classic" transport pathway. First, it was recently shown that this transport step is cytosol, energy, and temperature dependent, as expected for canonical intracellular transport (20). Second, early endosome-to-TGN transport is controlled by specific members of protein families found to be implicated at all levels of intracellular membrane exchange between compartments: the SNARE and the Rab proteins (20). Three t-SNARE proteins, syntaxin 6, syntaxin 16, and Vti1a, localized at the TGN and likely forming a functional complex, were found to interact physically and functionally with two early endosomal v-SNARE proteins, VAMP4 and, to a lesser extent, VAMP3/cellubrevin, to regulate the post-Golgi retrograde transport step. The GTPase Rab6a' was also implicated. Third, when analyzed by morphological methods, a large majority of cell-associated B subunit could be detected first in the Golgi apparatus and later in the ER (original work cited in Ref. 13).
In this context, it is important to note that at least one cellular protein of unknown function has been identified as a likely cargo for early endosome-to-TGN transport: the TGN marker TGN38/46 (original work cited in Ref. 13). TGN38 cycles between the TGN and the plasma membrane, and internalized antibodies against a tagged version of the protein can be detected in the early/recycling endosomes and the TGN but not late endosomes or lysosomes. Furthermore, anti-TGN38 antibody can be detected in the same structures as the B subunit during passage to the TGN, and interfering with syntaxin 16 or VAMP4 function not only inhibits B subunit transport to the TGN, but also that of TGN38 (20). Glycosyl phosphatidylinositol (GPI)-anchored proteins are candidates for early endosome-to-TGN transport as well. A model protein composed of green fluorescent protein linked to a GPI anchor was found to cycle between the plasma membrane and the TGN, without apparent passage via late endosomes (22). The apparent delivery of bacterial lipopolysaccharide to the Golgi apparatus may depend on the interaction of soluble CD14, with its GPI-anchored receptor (original work cited in Ref. 20). Surprisingly, other recent studies provide evidence for virus targeting to the retrograde route. Internalized adenoassociated virus could be detected in the Golgi cisternae of infected cells (2), and HIV gp120 protein interacts with Gb3, the Shiga toxin receptor (21). The question of whether the mannose 6-phosphate receptor (MPR) also uses the early endosome/TGN interface for its transport to the TGN remains controversial. Draper et al. (3) described an in vitro approach to monitor MPR endosome-to-TGN transport and observed that an interfering anti-clathrin antibody did not inhibit it. In apparent contrast, Schu and Thomas and their colleagues (see Ref. 20 for original references) described MPR relocalization from the TGN to the early endosome of intact cells on interference with the activity of the early endosome/TGN-localized AP1 clathrin adaptor. The latter observations appear interesting in light of ultrastructural findings on AP1/clathrin localization on membrane profiles of the early endosome, profiles in which the B subunit accumulates during its transport to the Golgi apparatus (13), suggesting that these AP1/clathrin coats participate in sorting into the retrograde route. When combined, these different data sets suggest that the MPR may take two different routes from endosomes to the TGN: the classic route from late endosomes, implicating the GTPase Rab9 and the new coat component TIP47, and the early endosome-to-TGN route. Do other toxins use the early endosome-TGN interface? For the moment, this question cannot be unambiguously answered. The other toxin whose transport has been studied in greater detail is the plant protein toxin ricin, for which the same biochemical tools as for Shiga toxin B subunit have been generated (original work cited in Ref. 13). It was shown that overexpression of dominant-negative dynamin inhibited ricin transport to the TGN, whereas a dominant-negative Rab9 mutant and ablation of clathrin expression had no effect (10). The situation was less clear for the recycling endosome-localized GTPase Rab11, for which overexpression of wild-type and a dominant-negative mutant had a partial inhibitor activity (10). The absence of effect with Rab9, a presumed marker for the MPR-specific pathway, and the partial inhibition observed with Rab11, similar to what has been described for the B subunit of Shiga toxin (28), argue that ricin might in fact take the early endosome-to-TGN pathway. However, more work will have to be done to establish this hypothesis. The question has been brought up whether the early endosome-to-TGN route leads via the recycling endosome. Very clearly, TGN38 and the B subunit of Shiga toxin both can be detected in the recycling endosome (original work cited in Ref. 13). The most convincing way to establish the importance of the recycling endosome in the post-Golgi retrograde transport step would be to show its inhibition through interference with the transport machinery of the recycling endosome. Two proteins have been identified as markers of the recycling endosome, although they can actually also be detected on the early sorting endosome: the v-SNARE VAMP3/cellubrevin and the GTPase Rab11. Interestingly, when the activity of both molecules was inhibited using different means, retrograde transport of Shiga toxin B subunit was only slightly perturbed (20, 28). In the case of Rab11, the use of wild-type, dominant-negative and dominant-activator mutants led to distinct morphological phenotypes that indicated that the protein might also have direct or indirect effects on the early sorting endosome (28). Although other interpretations can be envisioned, these data suggest that, at least for Shiga toxin B subunit (and possibly also ricin; see Ref. 10), passage via the recycling endosome is of minor importance for access to the TGN. It should also be pointed out that the exact nature of the recycling endosome still remains a matter of debate. Another controversy concerns the question of whether transferrin receptor-negative "early" endosomes exist in the post-Golgi retrograde route of Shiga toxin B subunit and other markers of this pathway (22). In what concerns the B subunit, this observation is in apparent contradiction with a previous report on the total overlap between transferrin receptor-containing endosomes and the B subunit internalized at low temperatures, a condition under which endocytosis still occurs but transport to the TGN is inhibited (see Ref. 13). This apparent contradiction could be resolved if one assumes that low-temperature internalization allows one to reveal phenomena that are too dynamic to be seen at 37°C, such as internalization of transferrin and B subunit into the same early endosomes before separation and binding of AP1/clathrin coats to early endosomal membranes. Again, another possibility is that cell-type differences account for the observed variations, with transferrin receptor-negative early endosomes being more or less abundant in different cells. However, in HeLa cells, at least two direct arguments suggest that the transferrin receptor containing early endosome is on the major B subunit transport route to the TGN. First, on overexpression of a dominant-negative mutant of Rab6a', transport to the TGN is almost totally blocked (20). Under these conditions, B subunit accumulates extensively in the transferrin receptor-positive early endosome and not in a transferrin receptor-negative compartment. Second, our unpublished observations show that B subunit arrival in the TGN is faster from the transferrin receptor-positive early endosome than from the plasma membrane.Unconventional transport. The recent excitement around Shiga toxin as a cell biology tool originates largely from the extensive targeting of this molecule into the retrograde route in certain cell types. However, it had been noted before that some cell types or cells of the same type under particular experimental conditions could show differences in the intracellular distribution of Shiga toxin, and Sandvig, Lingwood, and colleagues reported that these differential distributions correlated with the expression of different molecular species of the Shiga toxin receptor Gb3 under the respective conditions (original work cited in Ref. 13). However, these studies did not reveal how the expression of different molecular species of Gb3 would influence the intracellular distribution of Shiga toxin.
In this context, it appears of interest that recent studies have provided evidence for the association of Shiga toxin and its B subunit alone with membrane microdomains (see Refs. 4, 15, and references therein), commonly known as "lipid rafts," or under their biochemical denomination as "detergent-resistant membranes." The classic microdomain is composed of sphingolipids, cholesterol, and long-chain, saturated phospholipids. However, it seems likely today that microdomains of variable composition exist in biological membranes. Evidence was provided that B-subunit targeting into the retrograde route was dependent on association with microdomains, because it was shown that in human monocyte-derived macrophages and dendritic cells, the B subunit was not associated with microdomains and failed to be targeted into the retrograde route, as opposed to HeLa cells, in which the protein was microdomain associated and transported to the Golgi apparatus and the ER (4). Interestingly, this difference correlated with the observation that human monocytes, macrophages, and dendritic cells are totally resistant to Shiga toxin, despite Gb3 expression on these cells, as opposed to the highly toxin-sensitive HeLa cells (see Ref. 4 and references therein). In HeLa cells, destabilization of microdomains by cholesterol extraction reversibly inhibited B-subunit transport from the early endosome to the TGN (4). Under the same conditions, the recycling of the transferrin receptor was not affected, thus documenting the specificity of the observations. It appears tempting to speculate that different molecular species of Gb3 will associate with different efficiencies with microdomains, thus allowing one to modulate targeting into the retrograde route. Membrane microdomains may of course not only be of importance for sorting at the level of the early endosome, but may already play a role at the level of the plasma membrane, as recently suggested for the interleukin-2 receptor, the first microdomain-associated receptor that is efficiently sorted and internalized in a clathrin-independent manner (Fig. 1) (16).Golgi-to-ER transport. The mechanisms that allow targeting of Shiga toxin and its B subunit to the ER are less studied than those that govern transport at the early endosome-TGN interface. As mentioned above, Golgi-to-ER transport of the Shiga toxin appears to be independent of classic recycling markers, such as the KDEL receptor and the COPI coat, but dependent on the GTPase Rab6a (for review, see Refs. 12 and 26). The function of this newly discovered recycling route is still unclear, and a role for the maintenance of lipid homeostasis at the ER-Golgi interface has been suggested (26).
The KDEL receptor allows KDEL-tetrapeptide-tagged resident proteins to recycle from the Golgi apparatus to the ER. The addition of a KDEL signal on the B subunit clearly converts the molecule into a substrate for the KDEL receptor, and KDEL-bearing B subunits accumulate in the Golgi apparatus when KDEL-receptor trafficking is specifically inhibited (see references in Refs. 12 and 26). Two interpretations have to be considered to explain the latter result. On the one hand, the addition of the KDEL signal may shuffle the protein from its normal trafficking route to the KDEL-receptor route. In this scenario, the KDEL receptor would be dominant over the endogenous receptor. On the other hand, the KDEL-bearing B subunit may be transported from the TGN to the ER via its endogenous route. After its arrival in the ER, the protein would start cycling between the ER and the cis-Golgi, as shown for other resident proteins of the ER, and during this cycling, the protein may now become a ligand of the KDEL receptor (possibly after dissociation from its endogenous receptor). A critical question in this context is whether the B subunit remains associated with membrane microdomains until its arrival in the ER, the endpoint of the retrograde route. This question has not yet been addressed directly. The only existing evidence is the observation that even N-glycosylated, i.e., ER-associated, B subunit, is resistant to extraction with the anionic detergent Triton X-100 and floats on Optiprep gradients (4). Although indirectly, these data suggest that association with Gb3 is maintained all along the retrograde route. ![]() |
IN SEARCH OF A PHYSIOLOGICAL ROLE FOR THE SHIGA TOXIN RECEPTOR GB3 |
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The Shiga toxin receptor Gb3 has also been described as Burkitt's lymphoma antigen due to high expression levels on these cells, although some heterogeneity was also observed. Since then, elevated expression was also detected on other tumors (see Ref. 1 and references therein), such as ovarian cancers and astrocytoma cell lines. In a bacterial preparation with antineoplastic activity, Shiga toxin was identified as the active component (5). Astrocytoma cell growth in nude mice was significantly inhibited by Shiga toxin. Efforts are currently under way to evaluate Shiga toxin as a purging agent or to treat human cancers (1).
The marked expression of Gb3 in some tumors raises the
question of the physiological role of this lipid in addition to its established or presumed roles in toxin entry (see above) or HIV infection (see Ref. 12 for related references). Lingwood
and colleagues observed a limited sequence similarity between the B
subunit and the B cell differentiation marker CD19 and chain 1 of
interferon -receptors (see Ref. 13 for references).
Interfering with glycolipid metabolism affected both receptors. The
data on CD19 are of interest considering that germinal center B cells specifically express the lipid. More recently, similar types of studies
concluded that Gb3 might play a role in some aspects of cell adhesion (11) and MHC class II function
(7). More specific methods to manipulate Gb3
activity and the identification of other Gb3 binders may
allow obtaining definite information on the role of this lipid in
orchestrating trafficking and signaling functions in the normal and
malignant cells.
Indeed, an increasing number of studies implicates Gb3 ligation by Shiga toxin or by isolated B subunit in cellular signaling. The observed effects included induction of apoptosis (see Ref. 14 and references therein), cytokine and chemokine synthesis and release (Ref. 6 and references therein), and intracellular signaling cascades. The discussion of the possible implication of these signaling events in the establishment of toxin-related disease would go beyond the scope of this review. Furthermore, it might be mentioned that a critical point will be to relate these signaling events to the endogenous function of the lipid.
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SHIGA TOXIN B SUBUNIT AS A TOOL TO INTRODUCE ANTIGENS INTO THE MHC CLASS I PATHWAY |
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Dendritic cells have the exquisite capacity to induce a primary
immune response. Surprisingly, they can present antigens that have been
synthesized but not secreted by other cells, a phenomenon that has been
termed "cross-presentation" (9). The molecular mechanisms underlying this astonishing capacity are still largely unknown. The critical part about the cross-presentation process is that
induction of an efficient response against many viruses, and indeed
tumors, depends on antigenic protein(s) being introduced into the
cytosol of the antigen-presenting cell to be processed correctly by the
proteasome and to be loaded in a transporter associated with
antigen presentation (TAP)-dependent manner on neosynthesized class I
molecules in the lumen of the ER (Fig. 2). After transport to the cell
surface, peptide-loaded class I molecules can then interact with
cytotoxic T lymphoctes (CTL) in a reaction implicating costimulatory
molecules and MHC class II-dependent interaction with CD4+
helper T lymphocytes, which eventually leads to CTL activation (17). Activated CTL are capable of directly destroying
target cells that harbor intracellular pathogens or that present
genetic or somatic abnormalities, such as tumor cells.
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In the light of an important role for the immune system in the control of tumors, several approaches have been designed to mount an immunotherapeutic antitumor response. Until now, immunotherapy protocols in humans have mostly been based on live vectors such as viruses. However, considering health risks to immunosuppressed patients and environmental risks, the broad use of these techniques appears difficult. Furthermore, the high intrinsic immunogenicity of these vectors limits their efficiency. Several nonlive vectors have been evaluated for use in antigen presentation, and some, such as the heat-shock proteins, have reached the clinics (for reviews on other methods, see Ref. 27).
As mentioned above, the critical question for vector development for antigen presentation is the targeting of the antigenic protein into the cytosol of dendritic cells. Toxins have naturally evolved to solve the membrane translocation issue, which identifies them as potential tools for the development of novel approaches to antitumor and antiviral immunotherapy. Several toxins, such as Shiga toxin, Pertussis adenylate cyclase toxin, and anthrax toxin, have been used for antigen presentation studies (for a review, see Ref. 25a). In the following part of the review, progress made on the Shiga toxin B subunit system will be summarized.
In vitro antigen-presentation studies showed that MHC class I-restricted antigenic peptides, coupled to the B subunit, are presented by human and mouse dendritic cells (see Ref. 8 and references therein). The presentation is proteasome and TAP dependent, which indicates that the antigenic peptide is introduced into the endogenous class I presentation pathway (Fig. 2). These functional data are correlated with the labeling of B subunit on the nucleoli of antigen-presenting cells, confirming passage into the cyto/nucleoplasm (4). In nonprofessional antigen-presenting cells, i.e., HeLa cells, it was shown that antigenic peptide coupled to the A subunit of Shiga toxin was also presented in an MHC class I-restricted manner (23). However, the exact mechanism by which this occurred remains to be determined, and it is not yet known whether the B subunit as well could function as a peptide vector to the endogenous MHC class I antigen-presentation pathway in these cells.
Apart from membrane translocation, another critical issue for vector
development in immunotherapy is targeting of dendritic cells. In mice,
>26% of CD11c-positive dendritic cells express the Shiga toxin
receptor, whereas <1% of the splenocytes and nonpurified bone marrow
cells have detectable amounts of Gb3 at their surface (8). Quantitative analysis confirmed the presence of
Gb3 in human monocytes and monocyte-derived dendritic cells
and macrophages (see Ref. 4 and references therein). The
Shiga system, much like Pertussis adenylate cyclase toxin (see
references within Ref. 25a), may therefore allow
preferential targeting to dendritic cells as opposed to most other
toxins that have ubiquitously expressed receptors. Furthermore, mature
dendritic cells appear to boost a specific immune response more
efficiently than their immature precursors. In this context, it appears
of interest that Shiga toxin B subunit stimulates the production of
proinflammatory cytokines, such as tumor necrosis factor- (see
references within Refs. 4 and 13), capable of inducing
dendritic cell maturation.
CD4+ T cells are necessary to elicit a lasting memory T cell immunity and have been shown to contribute to an efficient antitumor response. The fact that Shiga toxin B subunit enters the lysosomal pathway in dendritic cells (4) suggests that it may introduce antigenic peptides into the class II-restricted pathway in addition to its capacity to induce class I-restricted antigen presentation.
Another critical issue concerns the production of anti-B subunit antibodies that might neutralize dendritic cell targeting and/or intracellular transport. It has been described that in mice, the anti-B subunit antibody response is allele specific. In humans, of all subjects that have been exposed to Shiga toxin, only a fraction produce antibodies (19). Shiga toxin B subunit thus appears to have evolved to minimize detection by antibodies, an understandable feature considering that the protein has to pass through the body's circulation system to reach its target cells.
In summary, the B subunit has a number of characteristics that seem to predispose the molecule as a vector for antigen presentation: apparent absence of toxicity, dendritic cell targeting, introduction of antigen into the endogenous MHC class I-restricted antigen-presentation pathway, and low immunogenicity. Furthermore, on injection of mice with a fusion protein consisting of the B subunit coupled to an antigenic model peptide, CTL specific for this peptide were induced, whereas this was not the case in mice injected with the peptide alone (8). Future studies will allow evaluating the B subunit as a vector in tumor protection models and ultimately in the clinical setting.
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ACKNOWLEDGEMENTS |
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C. Lamaze is acknowledged for critical reading of the manuscript.
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FOOTNOTES |
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This work was supported by grants from the Association pour la Recherche contre le Cancer (ARC-9028), the French Ministry of Science (ACI-5233 Jeunes Chercheurs), and the Fondation de France.
Due to a strict limitation on the number of references, this themes article cites mainly reviews and the most recent articles in the field. Many other important original papers are cited in the referenced review articles.
Address for reprint requests and other correspondence: L. Johannes, Traffic and Signaling Laboratory, Curie Institute, UMR144 Curie/CNRS, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
10.1152/ajpgi.00088.2002
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