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PNAS 106 (25): 10189-10194

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter

David J. Adle, Wenzhong Wei, Nathan Smith, Joshua J. Bies, and Jaekwon Lee1

The Redox Biology Center and Department of Biochemistry, University of Nebraska, Lincoln, NE 68588

Edited by Alexander Varshavsky, California Institute of Technology, Pasadena, CA, and approved May 7, 2009

Received for publication November 27, 2008.

Abstract: Cadmium is a highly toxic environmental contaminant that has been implicated in various disorders. A major mechanism for cadmium detoxification in the yeast Saccharomyces cerevisiae relies on extrusion via Pca1, a P-type ATPase. While an N-terminal degron targets Pca1 for degradation before its secretion to the plasma membrane, cadmium in the growth media rapidly up-regulates Pca1 by preventing its turnover. Here we show that the endoplasmic reticulum-associated degradation (ERAD) system, known for its role in quality control of secretory proteins, is unexpectedly responsible for the regulation of Pca1 expression by cadmium. Direct cadmium sensing at the ER by a degron in Pca1 leads to an escape of Pca1 from ERAD. This regulated conversion of an ERAD substrate to a secretory competent state in response to a cellular need illustrates a mechanism for expressional control of a plasma membrane protein. Yeast has likely evolved this mode of regulation for a rapid response against cadmium toxicity at the expense of constant synthesis and degradation of Pca1. ERAD of a portion of secretory proteins might occur via signal-dependent regulatory mechanisms as demonstrated for Pca1.

Key Words: ERAD • degron • P-type ATPase • Pca1 yeast

Author contributions: D.J.A. and J.L. designed research; D.J.A., W.W., N.S., and J.J.B. performed research; D.J.A. and J.L. analyzed data; and D.J.A. and J.L. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0812114106/DCSupplemental.

1To whom correspondence should be addressed. E-mail: jlee7{at}unlnotes.unl.edu

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