Error message

No crossref credentials set for pnas

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

PNAS, 23 June 2009
Vol. 106, Issue 25, p. 10189-10194
DOI: 10.1073/pnas.0812114106

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

  1. David J. Adle,
  2. Wenzhong Wei,
  3. Nathan Smith,
  4. Joshua J. Bies and
  5. Jaekwon Lee,1
  1. The Redox Biology Center and Department of Biochemistry, University of Nebraska, Lincoln, NE 68588
  1. Edited by Alexander Varshavsky, California Institute of Technology, Pasadena, CA, and approved May 7, 2009 (received for review November 27, 2008)


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.

  • ERAD
  • degron
  • P-type ATPase
  • Pca1 yeast


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


D. J. Adle, W. Wei, N. Smith, J. J. Bies, and J. Lee, Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter. PNAS 106, 10189-10194 (2009).

Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4
O. Foresti, A. Ruggiano, H. K. Hannibal-Bach, C. S. Ejsing, and P. Carvalho
elife 2, e00953-e00953 (1 January 2013)

Plastocyanin Controls the Stabilization of the Thylakoid Cu-transporting P-type ATPase PAA2/HMA8 in Response to Low Copper in Arabidopsis
W. Tapken, K. Ravet, and M. Pilon
J Biol Chem 287, 18544-18550 (25 May 2012)

How Saccharomyces cerevisiae copes with toxic metals and metalloids
R. Wysocki, and M. J. Tamas
FEMS Microbiol Rev 34, 925-951 (1 November 2010)

A Combined Zinc/Cadmium Sensor and Zinc/Cadmium Export Regulator in a Heavy Metal Pump
L. Baekgaard, M. D. Mikkelsen, D. M. Sorensen, J. N. Hegelund, D. P. Persson, R. F. Mills, Z. Yang, S. Husted, J. P. Andersen, M. J. Buch-Pedersen et al.
J Biol Chem 285, 31243-31252 (8 October 2010)

The Endoplasmic Reticulum-associated Degradation of the Epithelial Sodium Channel Requires a Unique Complement of Molecular Chaperones
T. M. Buck, A. R. Kolb, C. R. Boyd, T. R. Kleyman, and J. L. Brodsky
Mol. Biol. Cell 21, 1047-1058 (15 March 2010)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882