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Eeyarestatin 1 interferes with both retrograde and anterograde intracellular trafficking pathways
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Aletrari, Mina-Olga , McKibbin, Craig, Williams, Helen, Pawar, Vidya, Pietroni, Paola, Lord, Mike, Flitsch, Sabine L., Whitehead, Roger C., Swanton, Eileithyia, High, Stephen and Spooner, Robert A. (2011) Eeyarestatin 1 interferes with both retrograde and anterograde intracellular trafficking pathways. PLoS One, Vol.6 (No.7). e22713. doi:10.1371/journal.pone.0022713 ISSN 1932-6203.
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Official URL: http://dx.doi.org/10.1371/journal.pone.0022713
Abstract
Background: The small molecule Eeyarestatin I (ESI) inhibits the endoplasmic reticulum (ER)-cytosol dislocation and
subsequent degradation of ERAD (ER associated protein degradation) substrates. Toxins such as ricin and Shiga/Shiga-like
toxins (SLTx) are endocytosed and trafficked to the ER. Their catalytic subunits are thought to utilise ERAD-like mechanisms
to dislocate from the ER into the cytosol, where a proportion uncouples from the ERAD process, recovers a catalytic
conformation and destroys their cellular targets. We therefore investigated ESI as a potential inhibitor of toxin dislocation.
Methodology and Principal Findings: Using cytotoxicity measurements, we found no role for ESI as an inhibitor of toxin
dislocation from the ER, but instead found that for SLTx, ESI treatment of cells was protective by reducing the rate of toxin
delivery to the ER. Microscopy of the trafficking of labelled SLTx and its B chain (lacking the toxic A chain) showed a delay in
its accumulation at a peri-nuclear location, confirmed to be the Golgi by examination of SLTx B chain metabolically labelled
in the trans-Golgi cisternae. The drug also reduced the rate of endosomal trafficking of diphtheria toxin, which enters the
cytosol from acidified endosomes, and delayed the Golgi-specific glycan modifications and eventual plasma membrane
appearance of tsO45 VSV-G protein, a classical marker for anterograde trafficking.
Conclusions and Significance: ESI acts on one or more components that function during vesicular transport, whilst at least
one retrograde trafficking pathway, that of ricin, remains unperturbed.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QR Microbiology | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Library of Congress Subject Headings (LCSH): | Ricin, Endoplasmic reticulum, Biological transport | ||||
Journal or Publication Title: | PLoS One | ||||
Publisher: | Public Library of Science | ||||
ISSN: | 1932-6203 | ||||
Official Date: | 25 July 2011 | ||||
Dates: |
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Volume: | Vol.6 | ||||
Number: | No.7 | ||||
Page Range: | e22713 | ||||
DOI: | 10.1371/journal.pone.0022713 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Open Access (Creative Commons) | ||||
Date of first compliant deposit: | 18 December 2015 | ||||
Date of first compliant Open Access: | 18 December 2015 | ||||
Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), National Institutes of Health (U.S.) (NIH), Wellcome Trust (London, England) | ||||
Grant number: | BB/D005752/1 (BBSRC), 5U01AI65869-02 (NIH), 080566/Z/06/Z (WT) |
Data sourced from Thomson Reuters' Web of Knowledge
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