Shiga Toxin 1 Triggers a Ribotoxic Stress Response Leading to p38 and JNK Activation and Induction of Apoptosis in Intestinal Epithelial Cells

Smith, Wendy E.; Kane, Anne; Campbell, Sausan T.; Acheson, David W. K.; Cochran, Brent; Thorpe, Cheleste M.

doi:10.1128/iai.71.3.1497-1504.2003

Cited by 172 publications

(182 citation statements)

References 24 publications

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“…Paradoxically, this general blockade of mRNA translation is associated with the inducible release of various mediators of the inflammation (15,16). Several data support the concept that the Stx-dependent upregulation of proinflammatory genes in Gb3-positive epithelial cell lines occurs through the ribotoxic stress response since Stx, and other compounds possessing an N-glycosidase activity, induces cytokine release (25). Nonetheless, an alternative route for Stx transport exists in Gb-3-negative T84 cells (8), which does not lead to protein synthesis inhibition and cell death (7,8).…”

Section: Discussionmentioning

confidence: 83%

“…Therefore, it appears that the Gb-3 status of the cells is essential for the initiation of the signal transduction induced by Stx. In Gb-3-positive cells, Stx induces a MAPK-dependent induction of proinflammatory genes (15,25), whereas Stx inhibits NF-B signaling in Gb-3-negative enterocytes. Nonetheless, the mechanism by which Stx signals in human enterocytes remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Gobert

Vareille

Glasser³

et al. 2007

The Journal of Immunology

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Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli (EHEC) binds to endothelial cells expressing globotriaosylceramide-3 (Gb-3) and induces cell death by inhibiting translation. Nonetheless, the effects of Stx on human enterocytes, which lacks receptor Gb-3, remain less known. In this study, we questioned whether EHEC-derived Stx may modulate cellular signalization in the Gb-3-negative human epithelial cell line T84. Stx produced by EHEC was fixed and internalized by the cells. A weak activation of NF-κB was observed in T84 cells after EHEC infection. Cells infected with an isogenic mutant lacking stx1 and stx2, the genes encoding Stx, displayed an increased NF-κB DNA-binding activity. Consequently, the NF-κB-dependent CCL20 and IL-8 gene transcription and chemokine production were enhanced in T84 cells infected with the Stx mutant in comparison to the wild-type strain. Investigating the mechanism by which Stx modulates NF-κB activation, we showed that the PI3K/Akt signaling pathway was not induced by EHEC but was enhanced by the strain lacking Stx. Pharmacological inhibition of the PI3K/Akt signalization in EHEC ΔStx-infected T84 cells yielded to a complete decrease of NF-κB activation and CCL20 and IL-8 mRNA expression. This demonstrates that the induction of the PI3K/Akt/NF-κB pathway is potentially induced by EHEC, but is inhibited by Stx in Gb-3-negative epithelial cells. Thus, Stx is an unrecognized modulator of the innate immune response of human enterocytes.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Gobert

Vareille

Glasser³

et al. 2007

The Journal of Immunology

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“…Under these circumstances, JNK activation may influence important cellular consequences, such as alterations in gene expression (1,53,59,162,167,176,199,294,325,326,346), cell death (58,89,137,139,169,193,243,293), viral replication, persistent infection or progeny release (215,224,251,260), or altered cellular proliferation (178). The exact mechanism of JNK activation under each of these circumstances remains to be elucidated fully, although there may be involvement of Toll-like receptors, direct pathway modulation through interaction with upstream protein regulators, or the activation following an ER stress response (79,87,110,124,143,191,253,261,279,294,312).…”

Section: Fig 1 Overview Of the Jnk Pathway (A)mentioning

confidence: 99%

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

Bogoyevitch

Kobe

2006

Microbiol Mol Biol Rev

529

477

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SUMMARY The c-Jun N-terminal kinases (JNKs) are members of a larger group of serine/threonine (Ser/Thr) protein kinases from the mitogen-activated protein kinase family. JNKs were originally identified as stress-activated protein kinases in the livers of cycloheximide-challenged rats. Their subsequent purification, cloning, and naming as JNKs have emphasized their ability to phosphorylate and activate the transcription factor c-Jun. Studies of c-Jun and related transcription factor substrates have provided clues about both the preferred substrate phosphorylation sequences and additional docking domains recognized by JNK. There are now more than 50 proteins shown to be substrates for JNK. These include a range of nuclear substrates, including transcription factors and nuclear hormone receptors, heterogeneous nuclear ribonucleoprotein K, and the Pol I-specific transcription factor TIF-IA, which regulates ribosome synthesis. Many nonnuclear substrates have also been characterized, and these are involved in protein degradation (e.g., the E3 ligase Itch), signal transduction (e.g., adaptor and scaffold proteins and protein kinases), apoptotic cell death (e.g., mitochondrial Bcl2 family members), and cell movement (e.g., paxillin, DCX, microtubule-associated proteins, the stathmin family member SCG10, and the intermediate filament protein keratin 8). The range of JNK actions in the cell is therefore likely to be complex. Further characterization of the substrates of JNK should provide clearer explanations of the intracellular actions of the JNKs and may allow new avenues for targeting the JNK pathways with therapeutic agents downstream of JNK itself.

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“…In a number of other cell types induction of signaling leading to apoptosis seems to be mediated by the ribocytotoxic stress induced by the A-fragment after entry into the cytosol (Foster and Tesh, 2002;Smith et al, 2003). Thus, in the latter cases it takes time before the reported signaling takes place.…”

Section: Introductionmentioning

confidence: 99%

Shiga Toxin Regulates Its Entry in a Syk-dependent Manner

Lauvrak

Wälchli

Iversen

et al. 2006

MBoC

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Shiga toxin (Stx) is composed of an A-moiety that inhibits protein synthesis after translocation into the cytosol, and a B-moiety that binds to Gb3 at the cell surface and mediates endocytosis of the toxin. After endocytosis, Stx is transported retrogradely to the endoplasmic reticulum, and then the A-fragment enters the cytosol. In this study, we have investigated whether toxin-induced signaling is involved in its entry. Stx was found to activate Syk and induce rapid tyrosine phosphorylation of several proteins, one protein being clathrin heavy chain. Toxin-induced clathrin phosphorylation required Syk activity, and in cells overexpressing Syk, a complex containing clathrin and Syk could be demonstrated. Depletion of Syk by small interfering RNA, expression of a dominant negative Syk mutant (Syk KD), or treatment with the Syk inhibitor piceatannol inhibited not only Stx-induced clathrin phosphorylation but also endocytosis of the toxin. Also, Golgi transport of Stx was inhibited under all these conditions. In conclusion, our data suggest that Stx regulates its entry into target cells. INTRODUCTIONThe bacterial toxin Shiga toxin (Stx) inhibits protein synthesis in cells after first binding to Gb3 at the cell surface. Then, the toxin is endocytosed, and thereafter it is transported retrogradely to the Golgi apparatus and the endoplasmic reticulum (ER) before being translocated to the cytosol where it inactivates the ribosomes enzymatically (for reviews, see . The toxin is composed of two moieties: the enzymatically active A-chain that is noncovalently attached to a stable pentamer of B-chains that binds to Gb3 and mediates the endocytic uptake of the toxin. In some cells, Stx is endocytosed mainly by clathrin-dependent endocytosis , although other mechanisms exist (Nichols et al., 2001;Lauvrak et al., 2004;Saint-Pol et al., 2004). Importantly, the toxin can induce its own transport to clathrin-coated pits (Sandvig et al., 1989). When Stx is added to HeLa cells at 0°C, the toxin becomes evenly distributed at the cell surface. However, after a short incubation at 37°C, the toxin moves to clathrin-coated pits and is internalized. In toxin-sensitive cells a larger fraction of the toxin seems to be internalized from clathrin-coated pits at the cell surface, and clathrin is required for endosome-to-Golgi transport of the toxin as well (Lauvrak et al., 2004;Saint-Pol et al., 2004). Because it has been shown by different groups that the fatty acid of Gb3 is important for efficient Golgi transport (Sandvig et al., 1994;Lingwood, 1999), the composition of Gb3 also may play a role for the endocytic pathway used. A raft localization of StxB was recently found to be required for efficient retrograde transport (Falguieres et al., 2001).In some hematopoetic cells, Stx has been shown to trigger a rapid signaling cascade that might lead to apoptosis (for review, see Cherla et al., 2003). In a number of other cell types induction of signaling leading to apoptosis seems to be mediated by the ribocytotoxic stress induced by the A-fr...

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Shiga Toxin 1 Triggers a Ribotoxic Stress Response Leading to p38 and JNK Activation and Induction of Apoptosis in Intestinal Epithelial Cells

Abstract: Shiga toxins made by Shiga toxin-producing

Cited by 172 publications

References 24 publications

Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

Shiga Toxin Regulates Its Entry in a Syk-dependent Manner

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