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

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

Research output: Contribution to journalArticle

30 Scopus citations

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 upregulates 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.

Original languageEnglish (US)
Pages (from-to)10189-10194
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number25
DOIs
Publication statusPublished - Jun 23 2009

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Keywords

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

ASJC Scopus subject areas

  • General

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