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ToxSci Advance Access originally published online on July 23, 2009
Toxicological Sciences 2009 111(2):437-446; doi:10.1093/toxsci/kfp170
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Actin-Mediated Endocytosis Limits Intracellular Cr Accumulation and Cr Toxicity during Chromate Stress

Sara L. Holland and Simon V. Avery1

School of Biology, Institute of Genetics, The University of Nottingham, University Park, Nottingham, UK

1 To whom correspondence should be addressed. Fax: +44-115-951-3251. E-mail: simon.avery{at}nottingham.ac.uk.

Received May 15, 2009; accepted July 19, 2009


  Abstract

Chromate toxicity is well documented, but the underlying toxic mechanism(s) has yet to be fully elucidated. Following a Cr toxicity screen against > 6000 heterozygous yeast mutants, here we show that Cr resistance requires normal function of the cortical actin cytoskeleton. Furthermore, Cr-stressed yeast cells exhibited an increased number of actin patches, the sites of endocytosis. This was coincident with a marked stimulation of endocytosis following Cr exposure. Genetic dissection of actin nucleation from endocytosis revealed that endocytosis, specifically, was required for Cr resistance. A series of further endocytosis mutants (sac6{Delta}, chc1{Delta}, end3{Delta}) exhibited elevated Cr sensitivity. These mutants also showed markedly elevated cellular Cr accumulation, explaining their sensitivities. In wild-type cells, an initial endocytosis-independent phase of Cr uptake was followed by an endocytosis-dependent decline in Cr accumulation. The results indicate that actin-mediated endocytosis is required to limit Cr accumulation and toxicity. It is proposed that this involves ubiquitin-dependent endocytic inactivation of a plasma membrane Cr transporter(s). We showed that such an action was not dependent on the transporters that have been characterized to date, the sulfate (and chromate) permeases Sul1p and Sul2p.

Key Words: chromium toxicity; Arp2/3; latrunculin A; End3; sulfate transport; Saccharomyces cerevisiae.


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