Cholera toxin: mechanisms of entry into host cells...55 ExoU: A cytotoxin delivered by the type III secretion system of Pseudomonas aeruginosa ...

Transcription

1 Table of contents Diphtheria toxin, diphtheria-related fusion protein toxins, and the molecular mechanism of their action against eukaryotic cells...1 Ryan Ratts and John R. Murphy...1 Abstract Diphtheria toxin Catalytic domain delivery into the eukaryotic cytosol results in an inhibition of protein synthesis Receptor binding and substitution of the native diphtheria toxin receptor binding domain with surrogate ligands Intoxication of target cells requires the toxin to pass through a low ph endosomal compartment Internalization of the toxin by receptor mediated endocytosis The early endosomal compartment The transmembrane domain and channel formation The interchain disulfide bond Proposed mechanisms of diphtheria toxin C domain translocation Unassisted spontaneous translocation of the diphtheria toxin C domain A cytosolic translocation factor facilitates the membrane translocation of the diphtheria toxin C domain...12 References...14 Anthrax toxin and genetic aspects regulating its expression...21 Amy E. Tucker and Jimmy D. Ballard...21 Abstract Introduction Overview of anthrax toxin pxo1, the plasmid encoding AT The genes of anthrax toxin: paga, lef, and cya Environmental signals regulating AT expression AtxA, a global regulator of AT expression PagR, a negative regulator of PA expression AbrB, a growth phase-dependent regulator of AT production Conclusions and outlook...29 References...31 Shiga toxins and their mechanisms of cell entry...35 Kirsten Sandvig, Sébastien Wälchli, and Silje U. Lauvrak...35 Abstract Introduction Structure of Shiga toxins...37

2 VI Table of contents 3 Toxin interaction with cell surface receptors Endocytosis of Shiga toxins Endosome to Golgi transport of Shiga toxins Toxin transport from the trans-golgi network to the ER Furin-induced cleavage and activation of toxins Transport from ER to the cytosol Shiga toxin stimulates secretion of cytokines/chemokines Toxin-induced apoptosis Protection against Shiga toxin-induced disease Therapeutic use of Shiga toxins Conclusions Acknowledgements References Cholera toxin: mechanisms of entry into host cells David E. Saslowsky, Michael Kothe, and Wayne I. Lencer Abstract Introduction Toxin structure Retrograde transport into the Golgi and ER Possible mechanisms of ganglioside trafficking A direct pathway from TGN to ER Mechanisms of retro-translocation across the ER membrane Conclusions Acknowledgements References ExoU: A cytotoxin delivered by the type III secretion system of Pseudomonas aeruginosa Shira D. P. Rabin and Alan R. Hauser Abstract Introduction Discovery Activity Cell biological activity Enzymatic activity Mechanism of cytotoxicity Regulation ExoU secretion as a variable trait Role in virulence Role in human disease Conclusion References... 83

3 Table of contents VII Staphylococcal alpha-toxin...91 Sucharit Bhakdi, Iwan Walev, Matthias Husmann, and Angela Valeva...91 Abstract Occurrence and biological significance Properties of native toxin Mechanism of action Binding Oligomerization Pore formation Structure Structure of the heptameric pore formed in detergent solution Structure of the membrane-bound oligomer Structurally related pore-forming toxins Cellular resistance and repair mechanisms Biological effects Cytocidal action Secondary cellular reactions Long-range effects Synergism between alpha-toxin and other toxins Use of alpha-toxin in cell biology Medical relevance Acknowledgements References S. cerevisiae K28 toxin - a secreted virus toxin of the A/B family of protein toxins Susanne Leis, Jenny Spindler, Jochen Reiter, Frank Breinig, and Manfred J. Schmitt Abstract Introduction dsrna viruses cause a killer phenotype in S. cerevisiae Viral replication cycle Preprotoxin processing and toxin secretion Toxin uptake and retrograde transport A single disulfide bond between and exposes the ER targeting signal of the toxin Toxin dislocation out of the ER Mode of K28 toxin action Toxin-induced apoptotic host cell responses Toxin immunity Concluding remarks Acknowledgements References...127

4 VIII Table of contents Kluyveromyces lactis zymocin and other plasmid-encoded yeast killer toxins Raffael Schaffrath and Friedhelm Meinhardt Abstract Introduction The plasmid-encoded killer systemfrom Kluyveromyces lactis Plasmid structures, genome organizations, and gene functions Molecular genetic manipulation, gene shuffles, and applications The K. lactis zymocin complex Zymocin subunit composition and biogenesis Functional assignment of individual zymocin subunits Autoimmunity of K. lactis zymocin producers The zymocin response pathway of S. cerevisiae Target yeast spectrum and anti-proliferative effects Zymocin sensitivity conferring genes and zymocin resistance Zymocin docking and early response events Toxin-target capacity of the RNA polymerase II Elongator complex Other factors linked to Elongator s TOT function Zymocin mode of action: a working model Zymocin-related yeast killer systems Conclusions Acknowledgements References The Ustilago maydis killer toxins Jeremy Bruenn Abstract Introduction KP1 toxin Synthesis Structure, mechanism of action, and heterologous expression KP4 toxin Synthesis Structure Mechanism of action Heterologous expression KP6 toxin Synthesis Structure Mechanism of action Heterologous expression Summary References

5 Table of contents IX Zygocin a monomeric protein toxin secreted by virus-infected Zygosaccharomyces bailii Frank Weiler and Manfred J.Schmitt Abstract Zygocin is genetically encoded by a dsrna killer virus Zygocin is synthesized as an inactive precursor Zygocin toxicity involves disruption of cellular integrity Identification of host genes conferring zygocin resistance Zygocin as novel antimycotic Acknowledgements References Acidophilic structure and killing mechanism of the Pichia farinosa killer toxin SMKT Chise Suzuki Abstract Introduction Properties of a halotolerant killer yeast, Pichia farinosa SMKT with an acidophilic subunit structure SMKT consists of two distinct subunits SMKT preprotoxin encoded by the chromosomal gene and the maturation process Lethal effect of expression of SMK1 in S. cerevisiae Crystal structure of SMKT Stable state and dissociation process of SMKT P-type ATPase SPF1 required for sensitivity to SMKT SPF1 encoding a novel P-type ATPase Feature of type V P-type ATPases Localization of Spf1p Phenotypes of disruptants of SPF Comparison of intracellular roles of Spf1p and Pmr1p Killing and resistant mechanism of SMKT SMKT interacts with the cell surface of resistant cells Interaction of SMKT with cell membranes Concluding remarks Acknowledgements References...209

6 X Table of contents Ricin: structure, synthesis, and mode of action J. Michael Lord and Lynne M. Roberts Abstract Discovery Ricin structure Function of the ricin subunits Ricin biosynthesis Ricin intoxication of mammalian cells Endocytosis to the Golgi Golgi to ER transport Membrane translocation of ricin Concluding comments References

7