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

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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
Subjects:	Q Science > QR Microbiology
Divisions:	Faculty of 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:	Date Event 25 July 2011 Published
Date of first compliant deposit:	18 December 2015
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
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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