Sequential interactions with Sec23 control the direction of vesicle traffic

How the directionality of vesicle traffic is achieved remains an important unanswered question in cell biology. The Sec23p/Sec24p coat complex sorts the fusion machinery (SNAREs) into vesicles as they bud from the endoplasmic reticulum (ER). Vesicle tethering to the Golgi begins when the tethering factor TRAPPI binds to Sec23p. Where the coat is released and how this event relates to membrane fusion is unknown. Here we use a yeast transport assay to demonstrate that an ER-derived vesicle retains its coat until it reaches the Golgi. A Golgi-associated kinase, Hrr25p (CK1δ orthologue), then phosphorylates the Sec23p/Sec24p complex. Coat phosphorylation and dephosphorylation are needed for vesicle fusion and budding, respectively. Additionally, we show that Sec23p interacts in a sequential manner with different binding partners, including TRAPPI and Hrr25p, to ensure the directionality of ER-Golgi traffic and prevent the back-fusion of a COPII vesicle with the ER. These events are conserved in mammalian cells.     

Vaccination against and treatment of tuberculosis, the leishmaniases and AIDS: perspectives from basic immunology and immunity to chronic intracellular infections

The occurrence of infectious disease represents a failure of the immune system, a failure that must be prevented by effective vaccination or remedied by treatment. Vaccination against acute diseases such as smallpox and polio are very effective, due to the rapid and increased immune response of vaccinated individuals upon natural infection. In contrast, effective vaccination against intracellular pathogens that cause chronic diseases, such as the leishmaniases, tuberculosis and AIDS, has not been achieved. Clinical observations suggest cell-mediated, Th1 responses, exclusive of antibody production and the generation of Th2 cells, are optimally protective against these intracellular pathogens. Effective vaccination must ensure the generation of such a protective response. We explore here whether understanding very broad features of the regulation of the immune response can accommodate modern findings on the immunological features of these diseases, and provide a perspective within which strategies for effective vaccination and treatment can be developed.     

Expansion of amino acid homo-sequences in proteins: Insights into the role of amino acid homo-polymers and of the protein context in aggregation

Expansion of amino acid homo-sequences, such as polyglutamines or polyalanines, in proteins has been directly implicated in various degenerative diseases through a mechanism of protein misfolding and aggregation. However, it is still unclear how the nature of the expansion and the protein context influence the tendency of a protein to aggregate. Here, we have addressed these questions using spinocerebellar ataxia type-3 (ATX3) protein, the best characterised of the polyglutamine proteins, chosen as a model system. Using a transfected mammalian cell line, we demonstrate that ATX3 aggregation is noticeably reduced by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture and of the amino acid homo-sequence on pathology. Received 3 March 2006; received after revision 19 April 2006; accepted 22 May 2006     

Widespread occurrence of inhibitors of melanoma tyrosinase in plant and mammalian tissues

Résumé Les inhibiteurs de tyrosinase ont été trouvés dans des extraits de foie, de rein, de rate et de cerveau de rats et de souris, ainsi que dans des tumeurs amélanotiques S91, des sérums humains, des extraits de foie, de rein, de rate, de sein, et de peau humaine. Il y a au moins deux inhibiteurs: le premier, stable à la chaleur et dialysable, tandis que le second est labile à la chaleur et non-dialysable.

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This investigation was supported by the Medical Research Council of Canada, and the Ontario Cancer Treatment and Research Foundation. One of us (H.F.H.) is a Fellow of the Ontario Cancer Treatment and Research Foundation. The authors thank Mrs.H. Li and MissE. Santos for their skilful technical assistance.     

Clara cell surface of the rat: scanning and transmission electron microscopic study

Summary In normal young rats, groups of Clara cells in the bronchioles showed the formation of many cytoplasmic blebs on their cytoplasmic domes. Detached blebs rested on the bronchiolar epithelial cells. The scanning (SEM) and transmision electron microscope (TEM) studies suggest localized changes of Clare cell surface activities by increased formation of cytoplasmic blebs which may represent the apocrine type of secretion.This project was supported by research grants from NIH HD-10139 and the American Heart Association, Kansas Affiliate. We used the Electron Microscope Research Service Laboratory of the University of Kansas Medical Center.     

On the multiple sex chromosome mechanism in a lygaeid,Oxycarenus hyalinipennis (Costa)

Résumé Oxycarenus hyalinipennis (Costa) possède vraisemblablement des chromosomes sexuels multiples du typeX ₁ X ₂ Y. Les métaphases diploïdes renferment, soit 17, soit 19 éléments. Les 2 éléments supplémentaires des cinèses à 19, bien que comparables auxm-chromosomes des autres Lygéides, diffèrent de ces derniers en certains points de leur comportement qui évoque celui des «surnuméraires» trouvés chez d'autres insectes. La méiose est du type habituel chez les Hétéroptères.     

Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.

Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15-20 years and, at present, there is no effective treatment. The mutation in patients with Huntington's disease is an expanded CAG/polyglutamine repeat in huntingtin, a protein of unknown function with a relative molecular mass of 350,000 (M(r) 350K). The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset. The molecular pathways mediating the neuropathology of Huntington's disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine repeat develop a progressive syndrome with many of the characteristics of human Huntington's disease. Here we demonstrate evidence of caspase-1 activation in the brains of mice and humans with the disease. In this transgenic mouse model of Huntington's disease, expression of a dominant-negative caspase-1 mutant extends survival and delays the appearance of neuronal inclusions, neurotransmitter receptor alterations and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of the disease. In addition, we demonstrate that intracerebroventricular administration of a caspase inhibitor delays disease progression and mortality in the mouse model of Huntington's disease.