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J. Biol. Chem., Vol. 283, Issue 46, 31460-31468, November 14, 2008

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Expressional Control of a Cadmium-transporting P_1B-type ATPase by a Metal Sensing Degradation Signal^*

From the Redox Biology Center, Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588-0664

Cadmium is a highly toxic environmental contaminant implicated in various diseases. Our previous data demonstrated that Pca1, a P_1B-type ATPase, plays a critical role in cadmium resistance in yeast S. cerevisiae by extruding intracellular cadmium. This illustrates the first cadmium-specific efflux pump in eukaryotes. In response to cadmium, yeast cells rapidly enhance expression of Pca1 by a post-transcriptional mechanism. To gain mechanistic insights into the cadmium-dependent control of Pca1 expression, we have characterized the pathway for Pca1 turnover and the mechanism of cadmium sensing that leads to up-regulation of Pca1. Pca1 is a short-lived protein (t < 5 min) and is subject to ubiquitination when cells are growing in media lacking cadmium. Distinct from many plasma membrane transporters targeted to the vacuole for degradation via endocytosis, cells defective in this pathway did not stabilize Pca1. Rather, Pca1 turnover was dependent on the proteasome. These data suggest that, in the absence of cadmium, Pca1 is targeted for degradation before reaching the plasma membrane. Mapping of the N terminus of Pca1 identified a metal-responding degradation signal encompassing amino acids 250–350. Fusion of this domain to a stable protein demonstrated that it functions autonomously in a metal-responsive manner. Cadmium sensing by cysteine residues within this domain circumvents ubiquitination and degradation of Pca1. These data reveal a new mechanism for substrate-mediated control of P_1B-type ATPase expression. Cells have likely evolved this mode of regulation for a rapid and specific cellular response to cadmium.

Received for publication, August 5, 2008 , and in revised form, August 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK79209 (to J. L.) and P20RR-17657 (to the Nebraska Redox Biology Center). This work was also supported by funds provided through the Hatch Act in the University of Nebraska Research Division. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, University of Nebraska-Lincoln, N210 Beadle Ctr., Lincoln, NE 68588-0664. Tel.: 402-472-2658; Fax: 402-472-7842; E-mail: jlee7{at}unlnotes.unl.edu.

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				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, June 23, 2009; 106(25): 10189 - 10194. [Abstract] [Full Text] [PDF]