Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states

Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum

The plant cytotoxin ricin enters target mammalian cells by receptor-mediated endocytosis and undergoes retrograde transport to the endoplasmic reticulum (ER). Here, its catalytic A chain (RTA) is reductively separated from the cell-binding B chain, and free RTA enters the cytosol where it inactivates ribosomes. Cytosolic entry requires unfolding of RTA and dislocation across the ER membrane such that it arrives in the cytosol in a vulnerable, nonnative conformation. Clearly, for such a dislocated toxin to become active, it must avoid degradation and fold to a catalytic conformation. Here, we show that, in vitro, Hsc70 prevents aggregation of heat-treated RTA, and that RTA catalytic activity is recovered after chaperone treatment. A combination of pharmacological inhibition and cochaperone expression reveals that, in vivo, cytosolic RTA is scrutinized sequentially by the Hsc70 and Hsp90 cytosolic chaperone machineries, and that its eventual fate is determined by the balance of activities of cochaperones that regulate Hsc70 and Hsp90 functions. Cytotoxic activity follows Hsc70-mediated escape of RTA from an otherwise destructive pathway facilitated by Hsp90. We demonstrate a role for cytosolic chaperones, proteins typically associated with folding nascent proteins, assembling multimolecular protein complexes and degrading cytosolic and stalled, cotranslocational clients, in a toxin triage, in which both toxin folding and degradation are initiated from chaperone-bound states

Status of ZEPLIN II and ZEPLIN IV study

Abstract We discribe the construction status of ZEPLIN II detector, a 30-kg two-phase discriminating xenon detector to be installed in Boulby Mine, UK, for the direct detection of WIMP dark matter. Both scintillation and ionization will be measure in order to discriminate the radioactive background. ZEPLIN-II will have very high radioactive-background rejection efficiency. We will also discuss the study of ton scale ZEPLIN IV. The ZEPLIN program is a collaborative work of UCLA, TAMU, UKMDMC, and CNR Torino, Italy

Emerging New Crop Pests: Ecological Modelling and Analysis of the South American Potato Psyllid Russelliana solanicola (Hemiptera: Psylloidea) and Its Wild Relatives

© 2017 Syfert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Control of woolly aphid, Eriosoma lanigerum (Hausmann) (Hemiptera: Pemphigidae) on mature apple trees using insecticide soil-root drenches

Woolly aphid, Eriosoma lanigerum, is an important pest of apples that infests both the aerial and root parts of the tree. Root colonies are protected from the pesticide sprays applied during the growing season and the climatic effects of winter. Consequently, root colonies are a major source of aerial re-infestation in the following spring. Imidacloprid, the first of a new group of insecticides from the chloronicotinyl family, is known to provide excellent control of woolly aphid on trees up to 7-years-old when applied as a root soil drench. This study compared the effects of a single application of chlorpyrifos, imidacloprid, pirimicarb or vamidothion, applied as a root drench over four growing seasons. A soil wetting agent was added to each chemical to improve soil saturation and penetration. Imidacloprid provided excellent control of woolly aphid on the trees that were 17-years-old at the start of the study and continued to do so for four seasons. Pirimicarb appeared to offer some suppression of woolly aphid during the first season but not in subsequent seasons, while chlorpyrifos and vamidothion failed to control woolly aphid in any season. The potential role for imidacloprid in IPM programs is discussed