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The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain
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Pietroni, Paola, Vasisht, Nishi, Cook, Jonathan P., Roberts, David M., Lord, Mike, Hartmann-Petersen, Rasmus, Roberts, L. M. (Lynne M.) and Spooner, Robert A. (2013) The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain. Biochemical Journal, Volume 453 (Number 3). pp. 435-445. doi:10.1042/BJ20130133 ISSN 0264-6021.
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Official URL: http://dx.doi.org/10.1042/BJ20130133
Abstract
The plant cytotoxin ricin enters mammalian cells by receptor-mediated endocytosis, undergoing retrograde transport to the endoplasmic reticulum (ER) where its catalytic A chain (RTA) is reductively separated from the holotoxin to enter the cytosol and inactivate ribosomes. The currently accepted model is that the bulk of ER-dislocated RTA is degraded by proteasomes. We show here that the proteasome has a more complex role in ricin intoxication than previously recognised, that the previously reported increase in sensitivity of mammalian cells to ricin in the presence of proteasome inhibitors simply reflects toxicity of the inhibitors themselves, and that RTA is a very poor substrate for proteasomal degradation. Denatured RTA and casein compete for a binding site on the regulatory particle of the 26S proteasome, but their fates differ. Casein is degraded, but the mammalian 26S proteasome AAA-ATPase subunit RPT5 acts as a chaperone that prevents aggregation of denatured RTA and stimulates recovery of catalytic RTA activity in vitro. Furthermore, in vivo, the ATPase activity of Rpt5p is required for maximal toxicity of RTA dislocated from the Saccharomyces cerevisiae ER. Our results implicate RPT5/Rpt5p in the triage of substrates in which either activation (folding) or inactivation (degradation) pathways may be initiated.
Item Type: | Journal Article | ||||
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Alternative Title: | The proteasome cap prevents aggregation of ricin A chain | ||||
Subjects: | Q Science > QD Chemistry | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Library of Congress Subject Headings (LCSH): | Ricin , Endoplasmic reticulum, Cell organelles, Polypeptides, Biochemistry | ||||
Journal or Publication Title: | Biochemical Journal | ||||
Publisher: | Portland Press Ltd | ||||
ISSN: | 0264-6021 | ||||
Official Date: | 26 April 2013 | ||||
Dates: |
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Volume: | Volume 453 | ||||
Number: | Number 3 | ||||
Page Range: | pp. 435-445 | ||||
DOI: | 10.1042/BJ20130133 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Open Access (Creative Commons) | ||||
Date of first compliant deposit: | 24 December 2015 | ||||
Date of first compliant Open Access: | 24 December 2015 | ||||
Funder: | Wellcome Trust (London, England), Lundbeck Foundation, Novo Nordisk Foundation, Danish Council for Independent Research | ||||
Grant number: | 080566/7/06/Z (WT) |
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