Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter.
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.
Adle
David J
DJ
Department of Biochemistry, The Redox Biology Center, University of Nebraska, Lincoln, NE 68588, USA.
Wei
Wenzhong
W
Smith
Nathan
N
Bies
Joshua J
JJ
Lee
Jaekwon
J
D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D002104:Cadmium / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics
D027682:Cation Transport Proteins; C093603:PCA1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D002104:Cadmium; D000251:Adenosine Triphosphatases