Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae

Pathogenic microorganisms produce various virulence factors, e.g., enzymes, cytotoxins, effectors, which trigger development of pathologies in infectious diseases. Cholera toxin (CT) produced by O1 and O139 serotypes of Vibrio cholerae (V. cholerae) is a major cytotoxin causing severe diarrhea. Cholix cytotoxin (Cholix) was identified as a novel eukaryotic elongation factor 2 (eEF2) adenosine-diphosphate (ADP)-ribosyltransferase produced mainly in non-O1/non-O139 V. cholerae. The function and role of Cholix in infectious disease caused by V. cholerae remain unknown. The crystal structure of Cholix is similar to Pseudomonas exotoxin A (PEA) which is composed of an N-terminal receptor-recognition domain and a C-terminal ADP-ribosyltransferase domain. The endocytosed Cholix catalyzes ADP-ribosylation of eEF2 in host cells and inhibits protein synthesis, resulting in cell death. In a mouse model, Cholix caused lethality with severe liver damage. In this review, we describe the mechanism underlying Cholix-induced cytotoxicity. Cholix-induced apoptosis was regulated by mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways, which dramatically enhanced tumor necrosis factor-α (TNF-α) production in human liver, as well as the amount of epithelial-like HepG2 cancer cells. In contrast, Cholix induced apoptosis in hepatocytes through a mitochondrial-dependent pathway, which was not stimulated by TNF-α. These findings suggest that sensitivity to Cholix depends on the target cell. A substantial amount of information on PEA is provided in order to compare/contrast this well-characterized mono-ADP-ribosyltransferase (mART) with Cholix.

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Tumor necrosis factor-α and ceramide induce cell death through different mechanisms in rat mesangial cells

AJP Renal Physiology ◽

10.1152/ajprenal.1999.276.3.f390 ◽

1999 ◽

Vol 276 (3) ◽

pp. F390-F397 ◽

Cited By ~ 2

Author(s):

Yan-Lin Guo ◽

Baobin Kang ◽

Li-Jun Yang ◽

John R. Williamson

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Mesangial Cells ◽

Tnf Α ◽

Induced Apoptosis ◽

Factor Α ◽

Necrosis Factor

It has been proposed that ceramide acts as a cellular messenger to mediate tumor necrosis factor-α (TNF-α)-induced apoptosis. Based on this hypothesis, it was postulated that resistance of some cells to TNF-α cytotoxicity was due to an insufficient production of ceramide on stimulation by TNF-α. The present study was initiated to investigate whether this was the case in mesangial cells, which normally are insensitive to TNF-α-induced apoptosis. Our results indicate that although C2ceramide was toxic to mesangial cells, the cell death it induced differed both morphologically and biochemically from that induced by TNF-α in the presence of cycloheximide (CHX). The most apparent effect of C2ceramide was to cause cells to swell, followed by disruption of the cell membrane. It is evident that C2ceramide caused cell death by necrosis, whereas TNF-α in the presence of CHX killed the cells by apoptosis. C2ceramide did not mimic the effects of TNF-α on the activation of c-Jun NH2-terminal protein kinase and nuclear factor-κB transcription factor. Although mitogen-activated protein kinase [extracellular signal-related kinase (ERK)] was activated by both C2ceramide and TNF-α, such activation appeared to be mediated by different mechanisms as judged from the kinetics of ERK activation. Furthermore, the cleavage of cytosolic phospholipase A2during cell death induced by C2ceramide and by TNF-α in the presence of CHX showed distinctive patterns. The present study provides evidence that apoptosis and necrosis use distinctive signaling machinery to cause cell death.

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Interleukin-1β and Tumor Necrosis Factor (TNF)-α Sensitize Human Thyroid Epithelial Cells to TNF-Related Apoptosis-Inducing Ligand-Induced Apoptosis through Increases in Procaspase-7 and Bid, and the Down-Regulation of p44/42 Mitogen-Activated Protein Kinase Activity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030697 ◽

2004 ◽

Vol 89 (1) ◽

pp. 250-257 ◽

Cited By ~ 18

Author(s):

Emese Mezosi ◽

Su He Wang ◽

Saho Utsugi ◽

Laszlo Bajnok ◽

James D. Bretz ◽

...

Keyword(s):

Protein Kinase ◽

Tumor Necrosis ◽

Kinase Activity ◽

Mitogen Activated Protein Kinase ◽

Human Thyroid ◽

Protein Kinase Activity ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Induced Apoptosis ◽

Necrosis Factor

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Hepatitis B Virus Core Protein Sensitizes Hepatocytes to Tumor Necrosis Factor-Induced Apoptosis by Suppression of the Phosphorylation of Mitogen-Activated Protein Kinase Kinase 7

Journal of Virology ◽

10.1128/jvi.03106-14 ◽

2014 ◽

Vol 89 (4) ◽

pp. 2041-2051 ◽

Cited By ~ 22

Author(s):

Baosen Jia ◽

Minggao Guo ◽

Gaiyun Li ◽

Demin Yu ◽

Xinxin Zhang ◽

...

Keyword(s):

Hepatitis B Virus ◽

Protein Kinase ◽

Hepatitis B ◽

Mitogen Activated Protein Kinase ◽

Virus Core ◽

Tnf Α ◽

B Virus ◽

Mitogen Activated Protein ◽

Induced Apoptosis ◽

Necrosis Factor

ABSTRACTHepatitis B, which caused by hepatitis B virus (HBV) infection, remains a major health threat worldwide. Hepatic injury and regeneration from chronic inflammation are the main driving factors of liver fibrosis and cirrhosis in chronic hepatitis B. Proinflammatory tumor necrosis factor alpha (TNF-α) has been implicated as a major inducer of liver cell death during viral hepatitis. Here, we report that in hepatoma cell lines and in primary mouse and human hepatocytes, expression of hepatitis B virus core (HBc) protein made cells susceptible to TNF-α-induced apoptosis. We found by tandem affinity purification and mass spectrometry that receptor of activated protein kinase C 1 (RACK1) interacted with HBc. RACK1 was recently reported as a scaffold protein that facilitates the phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7) by its upstream activators. Our study showed that HBc abrogated the interaction between MKK7 and RACK1 by competitively binding to RACK1, thereby downregulating TNF-α-induced phosphorylation of MKK7 and the activation of c-Jun N-terminal kinase (JNK). In line with this finding, specific knockdown of MKK7 increased the sensitivity of hepatocytes to TNF-α-induced apoptosis, while overexpression of RACK1 counteracted the proapoptotic activity of HBc. Capsid particle formation was not obligatory for HBc proapoptotic activity, as analyzed using an assembly-defective HBc mutant. In conclusion, the expression of HBc sensitized hepatocytes to TNF-α-induced apoptosis by disrupting the interaction between MKK7 and RACK1. Our study is thus the first indication of the pathogenic effects of HBc in liver injury during hepatitis B.IMPORTANCEOur study revealed a previously unappreciated role of HBc in TNF-α-mediated apoptosis. The proapoptotic activity of HBc is important for understanding hepatitis B pathogenesis. In particular, HBV variants associated with severe hepatitis may upregulate apoptosis of hepatocytes through enhanced HBc expression. Our study also found that MKK7 is centrally involved in TNF-α-induced hepatocyte apoptosis and revealed a multifaceted role for JNK signaling in this process.

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Role of p38 Mitogen-activated Protein Kinase and Caspases in UV-B–induced Apoptosis of Murine Peritoneal Macrophages¶

Photochemistry and Photobiology ◽

10.1562/0031-8655(2004)79<48:ropmpk>2.0.co;2 ◽

2004 ◽

Vol 79 (1) ◽

pp. 48 ◽

Cited By ~ 2

Author(s):

Gautam Sethi ◽

Ajit Sodhi

Keyword(s):

Protein Kinase ◽

Peritoneal Macrophages ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

Murine Peritoneal Macrophages ◽

Induced Apoptosis

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Interleukin-6 Inhibits Fas-Induced Apoptosis and Stress-Activated Protein Kinase Activation in Multiple Myeloma Cells

Blood ◽

10.1182/blood.v89.1.227 ◽

1997 ◽

Vol 89 (1) ◽

pp. 227-234 ◽

Cited By ~ 185

Author(s):

Dharminder Chauhan ◽

Surender Kharbanda ◽

Atsushi Ogata ◽

Mitsuyoshi Urashima ◽

Gerrard Teoh ◽

...

Keyword(s):

Multiple Myeloma ◽

Protein Kinase ◽

Dna Fragmentation ◽

P38 Mapk ◽

Interleukin 6 ◽

Early Response ◽

Mitogen Activated Protein Kinase ◽

Serum Starvation ◽

Mapk Activity ◽

Induced Apoptosis

Abstract Fas belongs to the family of type-1 membrane proteins that transduce apoptotic signals. In the present studies, we characterized signaling during Fas-induced apoptosis in RPMI-8226 and IM-9 multiple myeloma (MM) derived cell lines as well as patient plasma cell leukemia cells. Treatment with anti-Fas (7C11) monoclonal antibody (MoAb) induced apoptosis, evidenced by internucleosomal DNA fragmentation and propidium iodide staining, and was associated with increased expression of c-jun early response gene. We also show that anti-Fas MoAb treatment is associated with activation of stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK); however, no detectable increase in extracellular signal-regulated kinases (ERK1 and ERK2) activity was observed. Because interleukin-6 (IL-6) is a growth factor for MM cells and inhibits apoptosis induced by dexamethasone and serum starvation, we examined whether IL-6 affects anti-Fas MoAb-induced apoptosis and activation of SAPK or p38 MAPK in MM cells. Culture of MM cells with IL-6 before treatment with anti-Fas MoAb significantly reduced both DNA fragmentation and activation of SAPK, without altering induction of p38 MAPK activity. These results therefore suggest that anti-Fas MoAb-induced apoptosis in MM cells is associated with activation of SAPK, and that IL-6 may both inhibit apoptosis and modulate SAPK activity.

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Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis

Blood ◽

10.1182/blood.v96.13.4142 ◽

2000 ◽

Vol 96 (13) ◽

pp. 4142-4151 ◽

Cited By ~ 108

Author(s):

Marcin Majka ◽

Anna Janowska-Wieczorek ◽

Janina Ratajczak ◽

M. Anna Kowalska ◽

Gaston Vilaire ◽

...

Keyword(s):

Protein Kinase ◽

Intracellular Signaling ◽

Phosphatidyl Inositol ◽

Mek Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Proliferative Effect ◽

Normal Human ◽

And Migration ◽

Induced Apoptosis

Abstract The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined. In this study it was found that SDF-1, unlike TPO, does not stimulate αIIbβ3+ cell proliferation or differentiation or have an antiapoptotic effect. However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO increase the adhesion of αIIbβ3+ cells to fibrinogen and vitronectin. Investigating the intracellular signaling pathways induced by SDF-1 and TPO revealed some overlapping patterns of protein phosphorylation/activation (mitogen-activated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-κB). It was also found that though inhibition of phosphatidyl-inositol 3-kinase (PI-3K) by LY294002 in αIIbβ3+ cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on the survival, proliferation, and migration of these cells. Hence, it is suggested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K–AKT axis is differentially involved in TPO- and SDF-1–dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1–regulated adhesion to fibrinogen and vitronectin, and SDF-1–mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses.

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