Globotriaosyl ceramide (CD77/Gb3) in the glycolipid-enriched membrane domain participates in B-cell receptor–mediated apoptosis by regulating Lyn kinase activity in human B cells

Mori, Tetsuya; Kiyokawa, Nobutaka; Katagiri, Yohko U.; Taguchi, Tomoko; Suzuki, Toyo; Sekino, Takaomi; Sato, Norihide; Ohmi, Kazuhiro; Nakajima, Hideki; Takeda, Tae; Fujimoto, Junichiro

doi:10.1016/s0301-472x(00)00538-5

Cited by 84 publications

(66 citation statements)

References 51 publications

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“…We therefore investigated whether Stx, although it binds a glycolipid receptor, can affect clathrin phosphorylation. It has previously been shown that Stx is able to induce a stimulation of tyrosine phosphorylation that peaks after 5 min in lymphocytes (Foster et al, 2000;Mori et al, 2000). Similarly, we found that also in HeLa cells Stx induced tyrosine phosphorylation of a variety of proteins even after 5 min of incubation (our unpublished data).…”

supporting

confidence: 81%

“…Because the tyrosine kinase Syk is activated by the StxB subunit in B cells (Mori et al, 2000), we decided to investigate whether Syk is activated during Stx entry into HeLa cells. It is known that Syk is present at a low concentration in HeLa cells (Renedo et al, 2001; our unpublished data) as well as in many other nonlymphoid cell lines (Yanagi et al, 2001).…”

Section: Syk Becomes Activated Upon Stx Bindingmentioning

confidence: 99%

“…Sequential activation of SFKs and Syk is necessary for both the uptake of the receptor into the cell (Park and Schreiber, 1995;Majeed et al, 2001;Strzelecka-Kiliszek et al, 2002) and for the trafficking to lysosomes (Bonnerot et al, 1998). Similarly, Stx in human B-cells activates at least two main tyrosine kinases, Lyn (a SFK) and Syk (Mori et al, 2000), and this activation occurs very fast. Also, in ACHN renal cells Stx activates the SFK Yes (Katagiri et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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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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supporting

confidence: 81%

Section: Syk Becomes Activated Upon Stx Bindingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Shiga Toxin Regulates Its Entry in a Syk-dependent Manner

Lauvrak

Wälchli

Iversen

et al. 2006

MBoC

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“…The content and organization of GSLs in membranes is tightly regulated (29,30). GSLs found in lipid rafts include GM1 and asialo-GM1 (ASGM1) (29,(31)(32)(33).…”

mentioning

confidence: 99%

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

et al. 2008

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We previously reported that respiratory syncytial virus (RSV) infection increases lung CD8 ϩ T cell GM1 expression. The related lipid asialo-GM1 (ASGM1) is expressed by T cells in viral infection and by natural killer (NK) cells. The in vivo co-expression of GM1 and ASGM1 by immune cells is not defined. Here we analyzed lung lymphocyte GM1 and ASGM1 expression in RSV-infected mice. GM1 and ASGM1 were coordinately upregulated by activated CD8 ϩ T cells in RSV-infected BALB/c and C57BL/6 mice. In contrast, RSV infection had no effect on constitutively high NK cell GM1 expression, while increasing NK cell ASGM1 expression. GM1 and ASGM1 co-localized in lipid raft structures in NK and CD8 ϩ T cells sorted from the lungs of RSV-infected mice. Anti-ASGM1 Ab treatment of RSV-infected BALB/c mice depleted GM1/ASGM1-expressing NK cells and GM1/ASGM1-expressing T cells, reduced lung IFN-␥ levels, increased viral load, delayed viral clearance, and reduced illness. STAT1 Ϫ/Ϫ mice are more susceptible to RSV replication and disease than wild-type mice. In RSV-infected STAT1 Ϫ/Ϫ mice, anti-ASGM1 Ab altered cytokine levels, but in contrast to BALB/c mice, antibody treatment had no effect on viral load or illness. Taken together, GM1 and ASGM1 expression are differentially regulated by T and NK cells in RSV infection. Also, GM1/ASGM1-expressing cells are important for control of RSV in BALB/c mice, whereas STAT1 Ϫ/Ϫ mice clear RSV by an alternative pathway. 327

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“…Interestingly, it has been shown that Stx binding rapidly activates several kinases, such as the Src kinases Yes [28,29] and Lyn [30], the tyrosine kinase Syk [30,31], the serine/threonine kinase PKC [32], and the MAP kinase p38 [33]. The activity of some of these kinases is important for Stx entry and intracellular transport, suggesting that Stx is able to induce its own transport (see below).…”

Section: Binding Of Stx To Cellular Membranesmentioning

confidence: 99%

The Intracellular Journey of Shiga Toxins

Torgersen¹

2013

TOTNJ

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Abstract:The Shiga toxin family consists of Shiga toxin (Stx) that is produced as a virulence factor by Shigella dysenteriae, and the Shiga-like toxins produced by certain strains of enterohemorrhagic E. coli as well as by some other types of bacteria. Infection with bacteria producing these toxins is a threat to human health even in industrialized countries, as the initial diarrhea caused by the infection might be followed by a complication named hemolytic uremic syndrome. The Shiga toxins consist of a binding moiety that in most cases binds to the glycosphingolipid Gb3 on the surface of susceptible cells, and an A-moiety responsible for the toxic effect in the cytosol. In order to reach its cytosolic target, the toxin must be internalized and then transported via the retrograde pathway to the Golgi complex and further to the endoplasmic reticulum. From the endoplasmic reticulum the enzymatically active part of the A-moiety is translocated to the cytosol, and cellular protein synthesis is inhibited. Although the Shiga toxins are involved in disease, they may also be exploited for medical diagnosis and treatment. Interestingly, the toxin receptor, Gb3, has a limited expression in normal tissues, but is overexpressed in several types of cancer. Thus, the use of Shiga toxin, or the binding part of the toxin, has great potential in cancer diagnostics and treatment. Furthermore, studies of the various uptake mechanisms and intracellular transport pathways exploited by the toxins, provide important insight in basic cell biology processes.

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Globotriaosyl ceramide (CD77/Gb3) in the glycolipid-enriched membrane domain participates in B-cell receptor–mediated apoptosis by regulating Lyn kinase activity in human B cells

Cited by 84 publications

References 51 publications

Shiga Toxin Regulates Its Entry in a Syk-dependent Manner

Shiga Toxin Regulates Its Entry in a Syk-dependent Manner

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

The Intracellular Journey of Shiga Toxins

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