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Published online 26 July 2004. doi:10.1083/jcb.200401157
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 3, 325-335
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Article

 Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function

Charissa D. Ellis1, Fudi Wang2, Colin W. MacDiarmid1, Suzanne Clark2, Thomas Lyons1, and David J. Eide1,2

1 Department of Biochemistry, University of Missouri, Columbia, MO 65211
2 Department of Nutritional Sciences, University of Missouri, Columbia, MO 65211

Address correspondence to David J. Eide, Dept. of Nutritional Sciences, 217 Gwynn Hall, University of Missouri, Columbia, MO 65211. Tel.: (573) 882-9686. Fax: (573) 882-0185. email: eided{at}missouri.edu

In this report, we show that zinc is required for endoplasmic reticulum function in Saccharomyces cerevisiae. Zinc deficiency in this yeast induces the unfolded protein response (UPR), a system normally activated by unfolded ER proteins. Msc2, a member of the cation diffusion facilitator (CDF) family of metal ion transporters, was previously implicated in zinc homeostasis. Our results indicate that Msc2 is one route of zinc entry into the ER. Msc2 localizes to the ER when expressed at normal levels. UPR induction in low zinc is exacerbated in an msc2 mutant. Genetic and biochemical evidence indicates that this UPR induction is due to genuine ER dysfunction. Notably, we found that ER-associated protein degradation is defective in zinc-limited msc2 mutants. We also show that the vacuolar CDF proteins Zrc1 and Cot1 are other pathways of ER zinc acquisition. Finally, zinc deficiency up-regulates the mammalian ER stress response indicating a conserved requirement for zinc in ER function among eukaryotes.

Key Words: zinc; transport; cation diffusion facilitator; endoplasmic reticulum; unfolded protein response

C.W. MacDiarmid's present address is R424 Research Building, Dept. of Biology, University of Missouri-St. Louis, One University Blvd., St. Louis, MO 63121-4499.

S. Clark's present address is F032A, 800 Hospital Dr., Dept. of Medicine-Endocrinology University of Missouri-Columbia, Columbia, MO 65211.

T. Lyons' present address is 404 Leigh Hall, Dept. of Chemistry, University of Florida, 127 Chemistry Research Building, P.O. Box 117200, Gainesville, FL 32611-7200.

Abbreviations used in this paper: CDF, cation diffusion facilitator; ERAD, ER-associated degradation; GPI, glycosylphosphatidylinositol; TPEN, N,N,N',N'-tetrakis-(2-pyridyl-methyl)ethylenediamine; UPR, unfolded protein response; ZRE, zinc-responsive element.


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