Diphtheria toxin, diphtheria-related fusion protein toxins, and the molecular mechanism of their action against eukaryotic cells

Ratts, Ryan; Murphy, John R.

doi:10.1007/b102267

Cited by 5 publications

(17 citation statements)

References 102 publications

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“…6) and involves (1) DT docking onto the cell surface receptor, (2) DT uptake and internalization by receptor-mediated endocytosis, (3) acidification of the endocytic vesicle by an ATP-driven proton pump, (4) uncoupling of fragment A from the A/B toxin and (5) delivery of the cytotoxic domain from the lumen of the endocytic vesicle into the cytosol (reviewed by Collier, 2001 andRatts &Murphy, 2005). Next, by virtue of its catalytic activity, fragment A of DT targets the eukaryotic translation elongation factor 2 (EF2) for NAD + -dependent ADP-ribosylation (Fig.…”

Section: Dt An A/b Prototype Toxin With Adp-ribosyltransferase Activitymentioning

confidence: 99%

“…7). Intriguingly, the EF2 analogues from the bacterial pathogens undergo no such diphthamide modification, which explains why C. diphtheriae cells are auto-immune and protected against their own ADP-ribosylase killer toxin (reviewed by Collier, 2001 andRatts &Murphy, 2005). its receptor binding (yellow) domain and is internalized by receptor-mediated endocytosis using clathrin-coated endosomes.…”

Section: Dt An A/b Prototype Toxin With Adp-ribosyltransferase Activitymentioning

confidence: 99%

“…This results in EF2 inactivation, inhibition of protein synthesis and eventually, death of the target cell. Scheme depiction has been inspired by previous DT reviews (for details see, Murphy, 1996;Collier, 2001;Todar 2004;Ratts & Murphy, 2005).…”

Section: Dt An A/b Prototype Toxin With Adp-ribosyltransferase Activitymentioning

confidence: 99%

“…Next and by virtue of its enzymatic activity, DT ADP-ribosylates its target protein, an irreversible modification that inactivates the essential function of EF2 in mRNA translation. Eventually, EF2 inactivation by DT causes depletion of de novo protein biosynthesis and results in the death of the target cell including the model eukaryote and budding yeast Saccharomyces cerevisiae (reviewed by Collier, 2001;Todar 2004;Ratts & Murphy, 2005). Here, we review recent advances in the molecular biology of DT and present new insights into DT mode of action and DT response pathway components.…”

Section: Introductionmentioning

confidence: 99%

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Diphtheria Disease and Genes Involved in Formation of Diphthamide, Key Effector of the Diphtheria Toxin

Uthman¹,

Liu²,

Giorgini³

et al. 2012

Insight and Control of Infectious Disease in Global Scenario

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Section: Dt An A/b Prototype Toxin With Adp-ribosyltransferase Activitymentioning

confidence: 99%

Section: Dt An A/b Prototype Toxin With Adp-ribosyltransferase Activitymentioning

confidence: 99%

Section: Dt An A/b Prototype Toxin With Adp-ribosyltransferase Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Diphtheria Disease and Genes Involved in Formation of Diphthamide, Key Effector of the Diphtheria Toxin

Uthman¹,

Liu²,

Giorgini³

et al. 2012

Insight and Control of Infectious Disease in Global Scenario

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“…The zymotoxin complex (zymocin) from Kluyveromyces lactis and the diphtheria toxin (DT) from Corynebacterium diphtheriae each cause cell death in Saccharomyces cerevisiae (Ratts and Murphy, 2005; Jablonowski and Schaffrath, 2007). Although the yeast toxin targets are distinct, the zymocin and DT sensitivity pathways share a gene that by complementation of a zymocin‐resistant mutant was identified as KTI11 ( K. lactis killer toxin insensitive 11) and later shown to be allelic with DPH3 ( diphthamide synthesis 3; Fichtner and Schaffrath, 2002; Liu et al ., 2004).…”

Section: Introductionmentioning

confidence: 99%

A versatile partner of eukaryotic protein complexes that is involved in multiple biological processes: Kti11/Dph3

Bär

Zabel

Liu

et al. 2008

Molecular Microbiology

103

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SummaryThe Kluyveromyces lactis killer toxin zymocin insensitive 11 (KTI11) gene from Saccharomyces cerevisiae is allelic with the diphthamide synthesis 3 (DPH3) locus. Here, we present evidence that the KTI11 gene product is a versatile partner of proteins and operates in multiple biological processes. Notably, Kti11 immune precipitates contain Elp2 and Elp5, two subunits of the Elongator complex which is involved in transcription, tRNA modification and zymocin toxicity. KTI11 deletion phenocopies Elongator-minus cells and causes antisuppression of nonsense and missense suppressor tRNAs (SUP4, SOE1), zymocin resistance and protection against the tRNase attack of zymocin. In addition and unlike Elongator mutants, kti11 mutants resist diphtheria toxin (DT), protect against ADP-ribosylation of eukaryotic translation elongation factor 2 (eEF2) by DT and induce resistance against sordarin, an eEF2 poisoning antifungal. The latter phenotype applies to all diphthamide mutants (dph1-dph5) tested and Kti11/Dph3 physically interacts with diphthamide synthesis factors Dph1 and Dph2, presumably as part of a trimeric complex. Moreover, we present a separation of function mutation in KTI11, kti11-1, which dissociates zymocin resistance from DT sensitivity. It encodes a C-terminal Kti11 truncation that almost entirely abolishes Elongator interaction without affecting association with Kti13, another Kti11 partner protein.

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Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

et al. 2011

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The synthesis of inactive enzyme precursors, also known as “zymogens,” serves as a mechanism for regulating the execution of selected catalytic activities in a desirable time and/or site. Zymogens are usually activated by proteolytic cleavage. Many viruses encode proteases that execute key proteolytic steps of the viral life cycle. Here, we describe a proof of concept for a therapeutic approach to fighting viral infections through eradication of virally infected cells exclusively, thus limiting virus production and spread. Using the hepatitis C virus (HCV) as a model, we designed two HCV NS3 protease-activated “zymogenized” chimeric toxins (which we denote “zymoxins”). In these recombinant constructs, the bacterial and plant toxins diphtheria toxin A (DTA) and Ricin A chain (RTA), respectively, were fused to rationally designed inhibitor peptides/domains via an HCV NS3 protease-cleavable linker. The above toxins were then fused to the binding and translocation domains of Pseudomonas exotoxin A in order to enable translocation into the mammalian cells cytoplasm. We show that these toxins exhibit NS3 cleavage dependent increase in enzymatic activity upon NS3 protease cleavage in vitro. Moreover, a higher level of cytotoxicity was observed when zymoxins were applied to NS3 expressing cells or to HCV infected cells, demonstrating a potential therapeutic window. The increase in toxin activity correlated with NS3 protease activity in the treated cells, thus the therapeutic window was larger in cells expressing recombinant NS3 than in HCV infected cells. This suggests that the “zymoxin” approach may be most appropriate for application to life-threatening acute infections where much higher levels of the activating protease would be expected.

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Diphtheria toxin, diphtheria-related fusion protein toxins, and the molecular mechanism of their action against eukaryotic cells

Cited by 5 publications

References 102 publications

Diphtheria Disease and Genes Involved in Formation of Diphthamide, Key Effector of the Diphtheria Toxin

Diphtheria Disease and Genes Involved in Formation of Diphthamide, Key Effector of the Diphtheria Toxin

A versatile partner of eukaryotic protein complexes that is involved in multiple biological processes: Kti11/Dph3

Engineered Toxins “Zymoxins” Are Activated by the HCV NS3 Protease by Removal of an Inhibitory Protein Domain

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