Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

If you need an accessible version of this item please contact JSTOR User Support

Cytosolic Chaperones Influence the Fate of a Toxin Dislocated from the Endoplasmic Reticulum

Robert A. Spooner, Philip J. Hart, Jonathan P. Cook, Paola Pietroni, Christian Rogon, Jörg Höhfeld, Lynne M. Roberts and J. Michael Lord
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 45 (Nov. 11, 2008), pp. 17408-17413
Stable URL: http://www.jstor.org/stable/25465291
Page Count: 6
  • Read Online (Free)
  • Cite this Item
If you need an accessible version of this item please contact JSTOR User Support
Cytosolic Chaperones Influence the Fate of a Toxin Dislocated from the Endoplasmic Reticulum
Preview not available

Abstract

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.

Page Thumbnails

  • Thumbnail: Page 
17408
    17408
  • Thumbnail: Page 
17409
    17409
  • Thumbnail: Page 
17410
    17410
  • Thumbnail: Page 
17411
    17411
  • Thumbnail: Page 
17412
    17412
  • Thumbnail: Page 
17413
    17413